ATHERO-ENDOCRINE-METABOLIC DISEASES

ATHERO-ENDOCRINE-METABOLIC DISEASES

PORTFOLIO 2021

3

Lipid metabolism disordersLipid metabolism disorders comprehensive panel [78 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]Familial hypercholesterolemia:

• Comprehensive panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

• Basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

• Basic panel [6 genes]Primary/polygenic hypertriglyceridemia and familial combined hyper-lipidemia [47 genes]Lipodystrophies [15 genes]Hypolipidemias [14 genes]

Endocrine disorders Endocrine disorders comprehensive panel [435 genes]Thyroid diseases [36 genes]Disorders of sex development, alterations in the hypothalamic-pituitary-gonadal axis, and infertility [125 genes]Adrenal diseases:Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. CYP21A2 (Sanger and MLPA) Adrenal diseases [53 genes]Diabetes and other pancreatic diseases:Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias [81 genes]

• Maturity-onset diabetes of the young (MODY) [15 genes]Pancreatitis and pancreatic insufficiency [15 genes]Pituitary disorders and short stature [88 genes] Phosphocalcic metabolism disorders [37 genes] Multi-endocrine disorders [6 genes]Monogenic obesity [70 genes]

Other genetic tests

Inborn errors of metabolism comprehensive panel [305 genes]Disturbances in the synthesis or catabolism of complex molecules comprehensive panel [202 genes]

• Lysosomal storage diseases [51 genes] Mucopolysaccharidosis [11 genes]Neuronal ceroid lipofuscinosis [13 genes]

• Peroxisomal disorders [36 genes]• Congenital disorders of glycosylation [102 genes]• Metal storage disorders [10 genes]

Toxic matter storage diseases comprehensive panel [68 genes]Energy deficiency metabolic diseases comprehensive panel [53 genes]

• Glycogenosis [30 genes]

Gene sequencingNextGenDx® massive sequencing (NGS)Exome sequencingMLPA testingSNP arrayArray CGHVariant segregation/Family studies

Early atherosclerosis and endocrine disorders Inborn errors of metabolism

Early atherosclerosis, endocrine disorders, and inborn errors of metabolismServices

Sequencing Panels

5

Sequencing panels

EARLY ATHEROSCLEROSIS, ENDOCRINE DISORDERS, AND INBORN ERRORS OF METABOLISM:

INBORN ERRORS OF METABOLISMEARLY ATHEROSCLEROSIS AND ENDOCRINE DISORDERS

ENDOCRINE DISORDERS COMPREHENSIVE PANEL [435 genes]

Thyroid disorders[36 genes]

Disorders of sex development, alterations in the hypotha-lamic-pitui-tary-gonadal axis, and infertility [125 genes]

Adrenal diseases: Diabetes and other pancreatic diseases:

Hypophysis disorders and short stature [88 genes]

Phospho-calcic metabolism disorders [37 genes]

Multi-en-docrine disorders [6 genes]

Monogenic obesity [70 genes]Monogenic

diabetes, hyperinsuli-nemias, and monogenic hypoglycemias [81 genes]

Pancreatitis and pancreatic insufficiency [15 genes]

Congenital adrenal hyper-plasia due to 21-hydroxylase deficiency. CYP21A2 (Sanger and MLPA)

Adrenal diseases [53 genes]

(Does not include sequencing of the CYP21A2 gene)

Maturity-onset diabetes of the young (MODY) [15 genes]

INBORN ERRORS OF METABOLISM COMPREHENSIVE PANEL [305 genes]

Disturbances in the synthesis or catabolism of complex molecules comprehensive panel [202 genes]

Toxic matter storage diseases comprehensive panel [68 genes]

Energy deficiency metabolic diseases comprehensive panel [53 genes]

Lysosomal storage diseases [51 genes]

Peroxisomal disorders [36 genes]

Congenital disorders of glycosylation [102 genes]

Metal storage disorders[10 genes]

Glycogenosis [30 genes]

Mucopoly-saccharidosis [11 genes]

Neuronal ceroid lipofuscinosis[13 genes]

LIPID METABOLISM DISORDERS COMPREHENSIVE PANEL[78 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Familial hypercholesterolemia: Primary/polygenic hypertri-glyceridemia and familial combined hyperlipidemia [47 genes]

Lipodystrophies[15 genes]

Primary hypolipidemias [14 genes]Comprehensive

panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Basic panel [6 genes]

7

Lipid metabolism disorders

The lipid metabolism disorders comprehensive panel is designed to identify patients with a high predisposition to develop early atherosclerotic disease with a familial presentation, which is currently regarded as a major global health issue by the WHO. Additionally, it includes variants in genes with pharmacogenetic implications related to adverse effects of conventional hypolipidemic agents (statins and fibrates), as well as 50 variants that allow assessing genetic susceptibility for developing coronary artery disease. It is especially aimed at patients with early atherosclerotic disease (men <55 years and women <65 years).

The genes included in the panel are responsible for monogenic diseases that alter lipid metabolism. Despite being considered rare diseases, they have a high impact on cardiovascular risk, as they act from very early stages of life and constitute a factor for poor prognosis in affected patients.

Approximately 9% of cardiac arrests in individuals younger than 65 years are estimated to be caused by monogenic dyslipidemias, mainly familial hypercholesterolemia. Identifying these monogenic diseases is essential, since the prognosis and, therefore, the clinical management of these patients can substantially differ from those of metabolic disorders originated by common causes (e.g., non-genetic dyslipidemias). Some of these diseases have widely variable phenotypic manifestations in certain families due to the presence of genes that modulate lipoprotein levels. Their knowledge is essential for a more accurate and personalized assessment of the risk associated with disease in members of a family.

Lipid metabolism disorders comprehensive panel [78 genes]

ABCA1 ABCG1 ABCG5 ABCG8 AGPAT2 AKT2 ANGPTL3 ANGPTL4 APOA1

APOA5 APOB APOC2 APOC3 APOE BSCL2 CAV1 CAVIN1 CIDEC

GPD1 GPIHBP1 HNF4A LCAT LDLR LDLRAP1 LIPA LIPC LIPE

LMF1 LMNA LPA LPL LRP6 MTTP MYLIP PCSK9 PLIN1

PNPLA2 PPARG PSMB8 STAP1 ZMPSTE24 ADD1 APOA2 APOA4 APOBEC1

ATF6 BUD13 CERS4 CETP CILP2 CRABP2 EPHX2 FABP2 FOXC2

FTO GALNT2 KLHL8 LEP LEPR MC4R PCDH15 PNPLA5 PON1

PPARA RXRG SAR1B SLC25A40 TCF7L2 TNFRSF1B TRIB1 USF1 WWOX

PLTP LMNB2 POLR3A SLC25A24 SCARB1 LIPG

Adequate coverage for structural variants and CNVs (copy-number variations).

It allows assessing the potential adverse effects of conventional pharmacological treatment with hypolipidemic agents(statins and fibrates). It includes variant in genes with pharmacogenetic implications.It allows assessing genetic susceptibility to develop coronary disease [50 variants]It includes genes associated with the following genotypes:

• Familial hypercholesterolemia and differential diagnoses• Primary hypertriglyceridemia and combined hyperlipidemia• Hypolipidemias and other phenotypes that can be considered modifiers of and/or protectors against cardiovas-

cular disease• Hyperalphalipoproteinemia• Lipodystrophies

Early atherosclerosis and endocrine disorders

LIPID METABOLISM DISORDERS COMPREHENSIVE PANEL[78 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Familial hypercholesterolemia: Primary/polygenic hypertri-glyceridemia and familial combined hyperlipidemia [47 genes]

Lipodys-trophies[15 genes]

Primary hypolipidemias [14 genes]Comprehensive

panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

Basic panel [6 genes]

lipid metabolism disorders I

9

Familial hypercholesterolemia (FH)

Familial hypercholesterolemia (FH) is a hereditary disease characterized by elevated LDL-C levels, early atherosclerosis, and increased early cardiovascular morbimortality. It constitutes one of the most prevalent monogenic diseases (1:500, or higher in some communities) and is recognized as a global healthcare issue by the WHO. It accounts for approximately 9% of cardiac arrests in individuals younger than 65 years and up to 20% of cardiac arrests in individuals younger than 45 years. In most cases, it follows an autosomal dominant inheritance pattern; therefore, 50% of members of a given family can be affected.

The identification of pathogenic mutations confirms the diagnosis of FH, according to the current diagnostic criteria, such as the British Simon Broome FH register, the Dutch Lipid Clinic Criteria, and the WHO-MEDPED criteria, all of them widely used for the diagnosis of this disease. Once a mutation has been identified in the proband, it is essential to initiate family screening, including pediatric members, in whom the benefits of early diagnosis and therapeutic intervention have been demonstrated.

Recent epidemiological studies have demonstrated that genetic testing for FH is highly cost-efficient and contributes to reduce long-term healthcare spending. Currently, in patients with high clinical suspicion, this study is indicated by multiple scientific communities and working groups on the subject at the international level and is integrated in population detection programs in different countries. Causative mutations for FH can be identified in up to 80% cases with defined clinical criteria for the disease.

Panels:

> Comprehensive panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

> Basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

> HF Basic panel [6 genes]

FH comprehensive panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

FH basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

13 GENES

5 GENES

• This panel includes the five main genes associated with FH and eight additional genes associated with hypercholesterolemia of possible monogenic etiology, as well as genetic variants included in the main polygenic risk scores for familial hypercholesterolemia.

• It allows for differential diagnosis in patients whose main biochemical alteration is hypercholesterolemia.• It includes the LPA gene, in which several variants conferring risk of coronary disease have been reported.• It allows estimating the risk of hypercholesterolemia of polygenic etiology in patients who have tested negative.• It is useful for providing adequate post-test genetic counseling for the family.• It allows assessing the potential adverse effects of conventional pharmacological treatment with hypolipidemic agents

(statins and fibrates).• It allows assessing genetic susceptibility to develop coronary disease [50 variants].

• This panel is aimed at patients with high phenotypic suspicion. It includes the five genes that are most prevalently associated with familial hypercholesterolemia (it does not test for diseases that constitute differential diagnoses of FH).

• It allows assessing the potential adverse effects of conventional pharmacological treatment with hypolipidemic agents (statins and fibrates).

• It allows assessing genetic susceptibility to develop coronary disease [50 variants].

LDLRAPOBPCSK9

LDLR

LDLRAP1APOE ABCG5

APOB

PHARMACOGENETICS (hypolipidemic agents)

PHARMACOGENETICS (hypolipidemic agents)

GENETIC RISK OF CORONARY DISEASE

GENETIC RISK OF CORONARY DISEASE

ABCG8CRABP2EPHX2

PCSK9

LIPALPAPNPLA5

LDLRAP1

STAP1

APOE



lipid metabolism disorders Ilipid metabolism disorders I

11

FH basic panel [6 genes]

LDLR APOB PCSK9 LDLRAP1 APOE SLCO1B1

1 Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, Harrison SC, Li K, Drenos F, Karpe F, Neil HA, Descamps OS, Langenberg C, Lench N, Kivimaki M, Whittaker J, Hingorani AD, Kumari M, Humphries SE. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Apr 13;381(9874):1293-3012 Futema M, Shah S, Cooper JA, Li K, Whittall RA, Sharifi M, Goldberg O, Drogari E, Mollaki V, Wiegman A, Defesche J, D'Agostino MN, D'Angelo A, Rubba P, Fortunato G, Waluś-Miarka M, Hegele RA, Aderayo Bamimore M, Durst R, Leitersdorf E, Mulder MT, Roeters van Lennep JE, Sijbrands EJ, Whittaker JC, Talmud PJ, Humphries SE. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem. 2015 Jan;61(1):231-8.3 Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG1, Cook NR, Chasman DI, Baber U, Mehran R, Rader DJ, Fuster V, Boerwinkle E, Melander O, Orho-Melander M, Ridker PM, Kathiresan S. Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. N Engl J Med. 2016 Dec 15;375(24):2349-23584 Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490ª5 Genest J, Hegele RA, Bergeron J, Brophy J, Carpentier A, Couture P, Davignon J, Dufour R, Frohlich J, Gaudet D, Gupta M, Krisnamoorthy P, Mancini J, McCrindle B, Raggi P, Ruel I, St-Pierre J (rimary Panel). Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can J Cardiol. 2014 Dec;30(12):1471-81. 6 Familial hypercholesterolaemia: identification and management. NICE guidelines https://www.nice.org.uk/guidance/cg717 Guidelines for the Diagnosis and Management of Familial Hypercholesterolaemia. The Cardiac Society of Australia and New Zealand. http://www.csanz.edu.au/wp-content/uploads/2014/12/Familial-Hypercholesterolaemia_2013-November.pdf8 Mata P, Alonso R, Ruiz A, Gonzalez-Juanatey JR, Badimón L, Díaz-Díaz JL, Muñoz MT, Muñiz O, Galve E, Irigoyen L, et al. Diagnóstico y tratamiento de la hipercolesterolemia familiar en España: documento de consenso. Atención Primaria, Volume 47, Issue 1, Pages 56-659 Hopkins PN, Toth PP, Ballantyne CM, Rader DJ; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S9-17 10 Centers for disease control and prevention (CDC). Public health genomics. Tier 1. Familial hypercholesterolemia: https://www.cdc.gov/genomics/implementa-tion/toolkit/fh_1.htm11 FH foundation (US). https://thefhfoundation.org/fh-diagnosis-management-and-family-screening

Hypertriglyceridemia is a frequently diagnosed disease in clinical practice and is generally of polygenic and multifactorial etiology. This biochemical alteration is currently accepted as a risk factor for cardiovascular atherosclerotic disease. Every 1 mmol/L (39 mg/dL) increase in triglyceride-rich particles (of genetic etiology) leads to a three-fold increase in risk of ischemic heart disease.An extremely high level of triglycerides may be due to familial or primary hypertriglyceridemia, caused by a point genetic defect (monogenic disease) transmitted following an autosomal recessive pattern.In some patients and relatives, hypertriglyceridemia can be accompanied by hypercholesterolemia, in which case the diagnosis could be familial combined hyperlipidemia (generally of polygenic etiology) or an underlying monogenic disease (such as primary hypertriglyceridemia or familial hypercholesterolemia). Occasionally, these phenotypes may even overlap, hence the need for differential diagnosis.This panel covers all the genes with a high degree of evidence of association with hypercholesterolemia or hypertriglyceridemia phenotypes with a strong genetic component.Included phenotypes:

• Primary hypertriglyceridemia (monogenic)

• Familial hypercholesterolemia (main genes)

• Combined hyperlipidemia/polygenic hypertriglyceridemia (markers)

Primary/polygenic hypertriglyceridemia and familial combined hyperlipidemia

ADD1 ANGPTL3 APOA1 APOA4 APOA5 APOB

APOBEC1 APOC2 APOC3 APOE ATF6 BUD13

CERS4 CETP CILP2 CRABP2 FABP2 FOXC2

FTO GALNT2 GPD1 GPIHBP1 HNF4A KLHL8

LCAT LDLR LEP LEPR LIPC LMF1

Primary/polygenic hypertriglyceridemia and familial combined hyperlipidemia panel [47 genes]


LPL LRP6 MC4R MYLIP PCDH15 PCSK9

PNPLA2 PON1 PPARA PPARG RXRG SLC25A40

TCF7L2 TNFRSF1B TRIB1 USF1 WWOX


This panel includes the five genes that are most prevalently associated with familial hypercholesterolemia (LDLR, APOB, PCSK9, LDLRAP1, APOE) and the main gene associated with statin-induced myopathy (SLCO1B1). It is aimed at patients with high phenotypic suspicion (it does not assess pathologies that constitute differential diagnoses of FH).


13

Lipodystrophies are a heterogeneous group of rare diseases with selective loss of adipose tissue as a common feature. However, they predispose to the development of metabolic complications similar to those observed in obesity.These include alterations in lipid metabolism (increased triglycerides and decreased HDL), as well as resistance to insulin and diabetes mellitus, entities associated with an increased risk of early atherosclerosis.

Lipodystrophies

Hypolipidemias are lipid metabolism disorders characterized by a decrease in plasma lipoprotein levels, which can be caused by either primary (genetic) or secondary factors. In primary disorders, one or several mutations may lead to hypoproduction or increased elimination of plasma LDL.The panel includes a group of genes associated with a marked decrease in the levels of the main lipoproteins.Mutations secondary to alterations in these genes may have a wide variety of clinical effects that predispose to ischemic cardiopathy (some genes associated with low LDL) or even have a cardiovascular protective effect (genes associated with decreased LDL), while others can be associated with nutritional pathologies (malabsorption, growth disorders, or vitamin deficiencies), liver diseases (fatty liver), etc.The coexistence of some variants in these genes with mutations that cause other genetic hyperlipidemias may lead to major phenotypic variability in some families, therefore affecting individual risk in carriers.Among the phenotypes are:

• Abetalipoproteinemia (Bassen-Kornzweig syndrome)

• Hypobetalipoproteinemia

• Chylomicron retention disease (Anderson disease)

Primary hypolipidemias

AGPAT2 AKT2

BSCL2 CAV1

CAVIN1 CIDEC

LMNA PLIN1

PPARG ZMPSTE24

Lipodystrophies panel [15 genes]

PSMB8 LIPE

LMNB2 POLR3A


ABCA1 ABCG1

ANGPTL3 ANGPTL4

APOA1 APOA2

APOB APOC3

LCAT MTTP

Hypolipidemias panel [14 genes]

MYLIP PCSK9

PLTP SAR1B


SLC25A24


15

Endocrine disorders comprehensive panel [436 genes, 4 chromosomal regions]

AAAS AARS2 ABCC8 ABCD1 ACAN ADCY3 ADRB1 ADRB2 ADRB3 AGPAT2 AGPS AIP AIRE AKR1C2 AKR1C4 AKT2 ALB ALMS1 ALPL AMELX AMH AMHR2 ANOS1 AP2S1 APC APOA5 APOC2 APPL1 AR ARL6 ARMC5 ARSB ARSE ARX ATP1A1 ATP2B3 ATRX BBIP1 BBS1 BBS10 BBS12 BBS2 BBS4 BBS5 BBS7 BBS9 BCOR BDNF BLK

15q25.3-q26.1

BLM BMP15 BSCL2 C8orf37 CACNA1D CARTPT CASR CAV1 CBX2 CCDC28B CDC73 CDK9 CDKN1A CDKN1B CDKN1C CDKN2B CDKN2C CEL CEP19 CEP290 CEP41 CFTR CHD4 CHD7 CIDEC CISD2 CLCN5 CLPP COL10A1 COL1A1 COL1A2 COL2A1 COL9A1 COL9A2 COMP COX4I2 CP CPA1 CPE CREBBP CRTAP CTNNB1 CTRC CTSK CUL3 CUL4B CUL7 CYB5A CYP11A1

CYP11B1 CYP11B2 CYP17A1 CYP19A1 CYP24A1 CYP27B1 CYP2R1 CYP3A4 DCAF17 DHCR7 DHH DMP1 DMRT1 DNAJC3 DPY19L2 DUOX2 DUOXA2 DUSP6 DYNC2H1 DYRK1B EBP EHHADH EIF2AK3 EIF2B5 EIF2S3 EMX2 ENPP1 EP300 ERCC3 ERCC6 ERCC8 ESR2 EXT1 EXT2 EZH1 FAM20C FEZF1 FGD1 FGF17 FGF23 FGF8 FGF9 FGFR1 FGFR2 FGFR3 FH FIG4 FLNB FLRT3

11p13

FMR1 FOXA2 FOXE1 FOXL2 FOXP3 FRAS1 FSHB FSHR FTO G6PC2 GALNS GALT GATA3 GATA4 GATA6 GCK GCM2 GH1 GHR GHRHR GHSR GLB1 GLI2 GLI3 GLIS3 GLUD1 GNA11 GNAS GNPAT GNPDA2 GNRH1 GNRHR GPC3 GPIHBP1 GUSB H6PD HADH HAMP HESX1 HFM1 HHAT HK1 HNF1A HNF1B HNF4A HS6ST1 HSD11B1 HSD11B2 HSD17B3

HSD17B4 HSD3B2 HSPG2 IDS IDUA IER3IP1 IFT172 IFT27 IFT74 IGF1 IGF1R IGFALS IGSF1 IL17RD IL2RA INS INSIG2 INSL3 INSR IRF6 IRS1 IRS4 IYD KCNJ11 KCNJ5 KDM6A KISS1 KISS1R KLB KLF11 KLHL3 KMT2D KRAS KRT8 LARS2 LEP LEPR LHB LHCGR LHX3 LHX4 LIFR LMF1 LMNA LRBA LTBP3 LZTFL1 MAFA MAGEL2

15q11-13

MAMLD1 MAP2K5 MAP3K1 MATN3 MC2R MC3R MC4R MCM4 MCM8 MCM9 MEN1 MKKS MKRN3 MKS1 MNX1 MRAP MRPS22 NBN NCOA1 NEGR1 NEUROD1 NEUROG3 NIPBL NKX2-1 NKX2-2 NKX2-5 NKX6-1 ISL1 NME1 NNT NOBOX NPPC NPR2 NPY NR0B1 NR0B2 NR2F2 NR3C1 NR5A1 NSMF NTRK2 NUP107 OTX2 P3H1 PAX4 PAX6 PAX8 PCBD1 PCSK1

17p11.2

PDE11A PDE8B PDX1 PEX7 PHEX PHF6 PHIP PICK1 PIK3R1 POU1F1 PLIN1 PMM2 PNLIP POLD1 POLG POLR3B POMC POR PPARG PPP1R15B PRKACA PRKAR1A PROK2 PROKR2 PROP1 PRSS1 PRSS2 PSMC3IP PTF1A PTH PTPN11 PYY RAF1 RAI1 RET RFX6 ROR2 RPL10 RPS6KA3 RPTOR RSPO1 RUNX2 RYR3 SAMD9 SLC34A1 SCNN1A SCNN1B SCNN1G SDCCAG8

SEC16B SECISBP2 SEMA3A SGK3 SGPL1 SH2B1 SHOX SIM1 SLC16A1 SLC16A2 SLC19A2 SLC26A2 SLC26A4 SLC26A7 SLC29A3 SLC2A2 SLC34A3 SLC40A1 SLC5A5 SLC6A14 SMARCAL1 SMC1A SMC3 SOHLH1 SOS1 SOX10 SOX2 SOX3 SOX9 SPATA16 SPINK1 SPRY4 SRD5A1 SRD5A2 SRY STAG3 STAR STAT3 STAT5B STX16 TAC3 TACR3 TBC1D4 TBCE TBL1X TBX1 TBX19 TCF7L2 TFR2

TG THRA THRB TMEM18 TMEM67 TOE1 TPO TRAPPC2 TRHR TRIM32 TRIM37 TRMT10A TRPM6 TRPS1 TRPV6 TSHB TSHR TSPYL1 TTC8 TTF1 TTF2 TTR TWNK TXNRD2 UBR1 UCP1 UCP2 UCP3 VDR VPS13B WDPCP WDR11 WFS1 WNK1 WNK4 WNT4 WRN WT1 ZBTB20 ZFP57 ZFPM2 ZMPSTE24 ZNRF3

Genes:

Chromosomal regions:

endocrine diseases I

The endocrine disorders comprehensive panel studies the most relevant genes related to the development of endocrine disorders.It includes:

• Thyroid disorders• Disorders of sex development, alterations in the hypothalamic-pituitary-gonadal axis, and infertility • Adrenal disorders• Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias• Pancreatitis and pancreatic insufficiency• Maturity-onset diabetes of the young (MODY)• Pituitary disorders and short stature• Phosphocalcic metabolism disorders• Multi-endocrine disorders

Endocrine disorders

Early atherosclerosis and endocrine disorders

ENDOCRINE DISORDERS COMPREHENSIVE PANEL [435 genes]

Thyroid disorders[36 genes]

Disorders of sex development, alterations in the hypotha-lamic-pitui-tary-gonadal axis, and infertility [125 genes]

Adrenal diseases: Diabetes and other pancreatic diseases:

Hypophysis disorders and short stature [88 genes]

Phospho-calcic metabolism disorders [37 genes]

Multi-en-docrine disorders [6 genes]

Monogenic obesity [70 genes]Monogenic

diabetes, hyperinsuli-nemias, and monogenic hypoglycemias [81 genes]

Pancreatitis and pancreatic insufficiency [15 genes]

Congenital adrenal hyper-plasia due to 21-hydroxylase deficiency. CYP21A2 (Sanger and MLPA)

Adrenal diseases [53 genes]

(Does not include sequencing of the CYP21A2 gene)

Maturity-onset diabetes of the young (MODY) [15 genes]

17

This panel studies the most relevant genes related to the development of thyroid disorders. Among those that cause hypothyroidism, it is worth noting thyroiddysgenesis, thyroiddyshormonogenesis, resistance to thyroid hormone, familial non-autoimmune hypothyroidism, and isolated thyroid-stimulating-hormone deficiency. These cases usually present as permanent congenital hypothyroidism. In some cases, such as Allan-Herndon-Dudley syndrome, thyroid dysfunction is associated with other malformations.

There are also some genetic diseases expressed as thyroid dysfunction, such as familial dysalbuminemic hyperthyroxinemia (increased T4 and T3 without clinical hyperthyroidism), familial non-autoimmune autosomal dominant hyperthyroidism (FNAH), and persistent sporadic non-autoimmune hyperthyroidism (PSNAH). The last two are usually associated with pathogenic variants in TSHR. Findings suggestive of a genetic etiology are: family history with an autosomal dominant inheritance pattern, absence of autoimmunity (autoantibodies [TRAB, anti-TPO], ophthalmopathy, dermopathy, lymphocyte infiltration), diffuse or multinodular goiter, and recurrence after antithyroid treatment (pharmacological, radioactive, or surgical). On the other hand, age at manifestation may be variable even within the same family (ranging between 0 and 60 years). The degree of hyperthyroidism may also vary.

Thyroid disorders

ALB DUOX2 DUOXA2 EZH1 FOXE1

GLIS3 GNAS HESX1 IGSF1 IRS4

IYD LHX3 LHX4 NKX2-1 NKX2-5

OTX2 PAX8 POU1F1 PRKAR1A PROP1

SECISBP2 SLC16A2 SLC26A4 SLC26A7 SLC5A5

Thyroid disorders panel [36 genes, 1 chromosomal region]

TBL1X TG THRA THRB TPO

TRHR TSHB TSHR TTF1 TTF2


TTR

15q25.3-q26.1

This panel studies the most relevant genes related to disorders of sex development (DSD), including all types of genital alterations as well as all discordances between chromosomal, gonadal, and genital sex. Most of them are cases of hypospadias (approximately 73%). Among newborns with atypical genitalia, 75% have a 46 XY karyotype, 10-15% have a 46 XX karyotype, and the rest have structural or numerical chromosome aberrations. Some of the phenotypes covered by this panel are:

• 46, XX gonadal dysgenesis• 46, XY gonadal dysgenesis• Androgen insensitivity syndrome• Aromatase deficiency• Male pseudohermaphroditism due to 5-alpha-reductase-2 deficiency

Likewise, it includes genes associated with alterations in the hypothalamic-pituitary-gonadal axis and infertility, such as:

• Hypogonadotropic hypogonadism• Early puberty• Premature ovarian failure• Male infertility due to teratozoospermia

Disorders of sex development, alterations in the hypothalamic-pituitary-gonadal axis, and infertility

Disorders of sex development, alterations in the hypothalamic-pituitary-gonadal axis, and infertility panel [126 genes, 1 chromosomal region]


AARS2 AKR1C2 AKR1C4 AMELX AMH AMHR2 ANOS1 AR ARX ATRX BCOR BMP15 CBX2 CDK9 CDKN1C CEP41

CHD4 CHD7 CLPP CREBBP CUL4B CYB5A CYP11A1 CYP11B1 CYP17A1 CYP19A1 DCAF17 DHCR7 DHH DMRT1 DPY19L2 DUSP6

DYNC2H1 EMX2 ERCC3 EIF2B5 ESR2 FEZF1 FGF17 FGF8 FGF9 FGFR1 FGFR2 FIG4 FLRT3 FOXL2 FRAS1 FSHB

FSHR GALT GATA4 GLI2 GNAS GNRH1 GNRHR HAMP HFM1 HHAT HS6ST1 HSD17B3 HSD17B4 HSD3B2 IL17RD INSL3

IRF6 KISS1 KISS1R KLB LARS2 LHB LHCGR LHX4 LMNA MAMLD1 MAP3K1 MCM8 MCM9 MKRN3 MKS1 MRPS22

NOBOX NR0B1 NR2F2 NR5A1 NSMF NUP107 PICK1 PMM2 POLG POLR3B POR PROK2 PROKR2 PROP1 PSMC3IP RPL10

RSPO1 SAMD9 SEMA3A SGPL1 SLC29A3 SLC40A1 SOHLH1 SOX10 SOX2 SOX3 SOX9 SPATA16 SPRY4 SRD5A1 SRD5A2 SRY

STAG3 STAR TAC3 TACR3 TFR2 TOE1 TSPYL1 TWNK WDR11 WT1 WNT4 ZFPM2 ZNRF3

11p13

endocrine diseases Iendocrine diseases I

19

21-hydroxylase deficiency, resulting in an inability to transform 17-hydroxyprogesterone into 11-deoxycortisol and progesterone into 11-deoxycortisone, accounts for 95% of adrenal hyperplasias. There are two clinical forms:

• Classic: simple virilizing and salt loss (1:15,000)• Non-classic: symptomatic and cryptic (1:1,000)

Due to the presence of the CYP21A1P pseudogene, testing for pathogenic variants in CYP21A2 requires a special approach.

Adrenal disorders

AAAS ABCD1 AIRE APC ARMC5 ATP1A1 ATP2B3

CACNA1D CDKN1C CTNNB1 CUL3 CYP11A1 CYP11B1 CYP11B2

CYP17A1 DHCR7 FH GNAS H6PD HESX1 HSD11B1

HSD11B2 HSD3B2 KCNJ5 KLHL3 LHX3 LHX4 MC2R

MCM4 MEN1 MRAP NNT NR0B1 NR3C1 NR5A1

Adrenal diseases panel [53 genes] (does not include sequencing of the CYP21A2 gene)

PDE11A PDE8B POU1F1 POMC POR PRKACA PRKAR1A

PROP1 SAMD9 SCNN1A SCNN1B SCNN1G SGPL1 STAR

TBX19 TXNRD2 WNK1 WNK4

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. CYP21A2 (Sanger and MLPA) There are two types of monogenic diabetes: MODY and neonatal diabetes. MODY is generally inherited in an autosomal dominant manner and represents approximately 1-2% of all cases of diabetes. Diagnosis is generally made before age 35 years, and, unlike in type 1 diabetes, insulin treatment is usually not necessary. Moreover, pancreatic islet-cell antibodies are not present, and neither is ketoacidosis, while it is common to observe evidence of endogenous insulin production after the honeymoon period (3-5 years after the diabetes starts). Conversely from type 2 diabetes, MODY is not usually associated with obesity or acanthosis nigricans. Genetic testing is useful for the proper management of the disease, determining the associated prognostic value (predictive value), and for differential diagnosis with other common forms of diabetes. Mutations causing MODY are identified in more than 90% of cases with a clear suspicion of the disease. Some forms of the disease also produce alterations in lipid metabolism. The risk of early atherosclerosis is increased in patients with MODY diabetes who are not receiving appropriate treatment. Neonatal diabetes is a rare disease in which diabetes starts during the first six months of life. This one is, in turn, transitory or permanent.

On the other hand, hyperinsulinemia and other causes of hypoglycemia, such as congenital hyperinsulinism, are caused by pathogenic variants in many of the genes associated with monogenic forms of diabetes.

Diabetes and other pancreatic diseases

Panels:

> Monogenic diabetes, hyper insulinemia and monogenic hypoglycemia [81 genes]

> Maturity-onset diabetes of the young (MODY) [15 genes]

Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias:


This panel studies the most relevant genes related to the development of the main phenotypes associated with defects in adrenal gland function. Many of these diseases are produced by alterations in specific enzymes leading to adrenal insufficiency, either primary or secondary, therefore causing different metabolic and sex development disorders. Phenotypes covered by this panel include:

• Congenital adrenal hyperplasia• Primary bilateral macronodular adrenal hyperplasia• X-linked adrenal hypoplasia congenita• Aldosterone-producing adenoma, familial glucocorticoid deficiency• Familial hyperaldosteronism• Proopiomelanocortin deficiency• Adrenoleukodystrophy • Allgrove syndrome (triple A) • Other enzyme defects associated with adrenal insufficiency


21

ABCC8 AGPAT2 AGPS AKT2 ALMS1 APPL1 BLK BSCL2 CACNA1D CAV1 CEL

ABCC8 APPL1

CIDEC CISD2 CP DCAF17 DNAJC3 DYRK1B EIF2AK3 EIF2S3 ENPP1 FOXA2 FOXP3

BLK CEL

G6PC2 GATA4 GATA6 GCK GLIS3 GLUD1 GPC3 HADH HAMP HK1 HNF1A

GCK HNF1A

HNF1B HNF4A IER3IP1 IL2RA INS INSIG2 INSR IRS1 ISL1 KCNJ11 KDM6A

HNF1B HNF4A

KLF11 KMT2D LMNA LRBA MAFA MNX1 NEUROD1 NEUROG3 NKX2-2 NKX6-1 PAX4

INS KCNJ11

Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias panel [81 genes]

Maturity-onset diabetes of the young (MODY) panel [15 genes]

PAX6 PCBD1 PDX1 PIK3R1 PLIN1 PMM2 POLD1 PPARG PPP1R15B PTF1A RFX6

KLF11 NEUROD1

RYR3 SLC16A1 SLC19A2 SLC29A3 SLC2A2 SLC40A1 STAT3 TBC1D4 TFR2 TRMT10A UCP2

PAX4 PDX1


This panel covers the following phenotypes:

• Monogenic diabetes: maturity-onset diabetes of the young (MODY) and neonatal diabetes

• Hyperinsulinemias

• Monogenic hyperinsulinemic hypoglycemia


This panel includes the most relevant genes associated with the development of maturity-onset diabetes of the young (MODY).

WFS1 ZBTB20 ZFP57 ZMPSTE24

RFX6

APOA5 APOC2

CASR CFTR

COX4I2 CPA1

CTRC GPIHBP1

KRT8 LMF1

Pancreatitis and pancreatic insufficiency panel [15 genes]

PNLIP PRSS1

PRSS2 SPINK1


UBR1

This panel includes the most relevant genes associated with the development of hereditary pancreatitis, familial pancreatitis, and pancreatic insufficiency. Genetic etiology of pancreatitis should be suspected after the common causes of pancreatitis are ruled out and in the case of compatible family history. It generally manifests at early ages (<35 years). A genetic test is recommended for a proband with pancreatitis when any of the following conditions are also met: unexplained episode of pancreatitis in childhood, recurrent pancreatitis of unknown cause, chronic pancreatitis of unknown cause (especially in those under 35 years of age without abusive consumption of alcohol), or a family member with a history of recurrent acute pancreatitis, chronic pancreatitis, or childhood pancreatitis episode of unknown cause.

Moreover, it can be used to test for other phenotypes, such as the following:

• Pancreatic insufficiency, anemia, or hyperostosis

• Pancreatic lipase deficiency

Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias: Pancreatitis and pancreatic insufficiency:


23

This panel studies genes associated with pituitary disorders with a greater level of evidence. Moreover, it also covers growth alterations and short stature. Among the most relevant tested phenotypes are:

• Panhypopituitarism

• Isolated growth hormone deficiency

• Growth delay due to IGF1 deficiency

• Laron syndrome

• Pallister-Hall syndrome

• Primary acid-labile subunit deficiency

• Pituitary adenoma

Pituitary disorders and short stature

ACAN AGPS AIP ALPL ARSB ARSE ATRX BLM COL10A1 COL1A1 COL1A2

COL2A1 COL9A1 COL9A2 COMP CREBBP CRTAP CTSK CUL7 DHCR7 EBP EP300

ERCC6 ERCC8 EXT1 EXT2 FGD1 FGF23 FGFR3 FLNB GALNS GH1 GHR

GHRHR GHSR GLB1 GLI2 GLI3 GNAS GNPAT GUSB HESX1 HSPG2 IDS

IDUA IGF1 IGF1R IGFALS INSR KDM6A KMT2D KRAS LHX3 LHX4 LIFR

Pituitary disorders and short stature panel [88 genes]

LTBP3 MATN3 NBN NIPBL NME1 NPPC NPR2 P3H1 PEX7 PHEX POU1F1

PROP1 PTPN11 RAF1 RAI1 ROR2 RPS6KA3 RUNX2 SHOX SLC26A2 SMARCAL1 SMC1A


SMC3 SOS1 SOX3 STAT5B TBCE TBX19 THRB TRAPPC2 TRIM37 TRPS1 WRN

AIRE ALPL AP2S1 CASR CDC73 CDKN1A

CDKN1B CDKN2B CDKN2C CLCN5 CYP24A1 CYP27B1

CYP2R1 CYP3A4 DMP1 EHHADH ENPP1 FAM20C

FGF23 GATA3 GCM2 GNA11 GNAS MEN1

PHEX PTH RET SGK3 SLC34A1 SLC34A3

Phosphocalcic metabolism disorders panel [37 genes]

SOX3 STX16 TBCE TBX1 TRPM6 TRPV6

VDR


This panel studies genes associated with parathyroid and phosphocalcic metabolism disorders with a higher level of evidence. Among the most relevant tested phenotypes are:

• Hyperparathyroidism

• Hypoparathyroidism

• Familial hypocalciuric hypercalcemia

• Autosomal dominant hypocalcemia

• Hypophosphatemic rickets

• Hypophosphatasia

• HRD syndrome

• Sanjad-Sakati syndrome

Phosphocalcic metabolism disorders


25

This panel studies genes with a greater level of evidence for pathologies that affect several endocrine glands at the same time , such as:

• Polyglandular autoimmune syndrome type 1

• Multiple endocrine neoplasia types 1 and 2

• Carney complex

• Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Multi-endocrine disorders

AIRE CDKN1B FOXP3 MEN1 PRKAR1A

Multi-endocrine disorders panel [6 genes]

RET


ADCY3 ADRB1 ADRB2 ADRB3 ALMS1 ARL6 BBIP1 BBS1 BBS10

17p11.2

BBS12 BBS2 BBS4 BBS5 BBS7 BBS9 BDNF CARTPT CCDC28B

15q11-13

CEP19 CEP290 C8orf37 CPE CUL4B DYRK1B FMR1 FTO GHSR

11p13

GNAS GNPDA2 IFT172 IFT27 IFT74 IRS1 LEP LEPR LZTFL1

MAGEL2 MAP2K5 MC3R MC4R MKKS MKS1 NEGR1 NPY NR0B2

Monogenic obesity panel [70 genes, 3 chromosomal regions]

NTRK2 PCSK1 PHF6 PHIP POMC PPARG PYY RAI1 RPTOR

SDCCAG8 SEC16B SH2B1 SIM1 SLC6A14 NCOA1 TCF7L2 TMEM18 TMEM67


TRIM32 TTC8 UCP1 UCP2 UCP3 VPS13B WDPCP

This panel includes the most relevant genes and genetic regions associated with monogenic obesity, as well as phenotypes that are associated with the development of obesity. Among the phenotypes are:

• Obesity due to proopiomelanocortin (POMC) deficiency

• Obesity due to leptin or leptin receptor deficiency

• Smith-Magenis syndrome

• Obesity due to melanocortin 4 receptor deficiency

• Alström syndrome

• Bardet–Biedl syndrome

• Prader-Willi syndrome

Monogenic obesity


27

Inborn errors of metabolism include a wide range of phenotypes that can be classified according to several criteria.

HealthinCode has developed panels organized in groups, taking these diagnostic criteria into account. Those genes with sufficient clinical evidence have been included.

Inborn errors of metabolism

INBORN ERRORS OF METABOLISM COMPREHENSIVE PANEL [305 genes]


Toxic matter storage diseases compre-hensive panel [68 genes]

Energy deficiency metabolic diseases compre-hensive panel [53 genes]

Lysosomal storage diseases [51 genes]

Peroxisomal disorders [36 genes]

Congenital disorders of glycosylation [102 genes]

Metal storage disorders[10 genes]

Glycogenosis [30 genes]

Mucopoly-saccharidosis [11 genes]

Neuronal ceroid lipofuscinosis[13 genes]

Inborn errors of metabolism comprehensive panel [305 genes]

ABAT ABCD1 ABCD3 ABHD5 ACAD8 ACADL ACADM ACADS ACADVL ACAT1 ACOX1 AGK AGL AGPS AGXT ALDH3A2 ALDH4A1 ALDH5A1 ALDOA ALDOB ALG1 ALG11 ALG12 ALG13 ALG14 ALG2 ALG3 ALG6 ALG8 ALG9 AMACR AMT APRT ARG1

ARSE ASPA ASS1 ATP13A2 ATP6AP1 ATP6V0A2 ATP7A ATP7B B3GALNT2 B3GALT6 B3GAT3 B3GLCT B4GALT1 B4GALT7 BCKDHA BCKDHB BMP2 BTD C1GALT1C1 CA5A CACNA1S CAD CAT CBS CCDC115 CHST14 CHST3 CHST6 CHSY1 CLCN1 CLDN16 CLN3 CLN5 CLN6

CLN8 COG1 COG2 COG4 COG5 COG6 COG7 COG8 CP CPOX CPT1A CPT2 CTSD CTSF CYP27A1 D2HGDH DBT DDOST DHDDS DLAT DNAJC12 DNAJC5 DNM1L DOLK DPAGT1 DPM1 DPM2 DPM3 DYM EBP ENO3 EPM2A ETFA ETFB

ETFDH ETHE1 EXT1 EXT2 FAH FAR1 FBP1 FECH FH FKRP FKTN FMO3 FTH1 FUT8 FXYD2 G6PC GAA GALE GALK1 GALNT12 GALNT3 GALT GAMT GBE1 GCDH GCSH GFPT1 GLDC GLS GLUL GMPPA GMPPB GNE GNMT

GNPAT GORAB GRHPR GRN GSS GYG1 GYS1 GYS2 HADHA HADHB HAL HAMP HFE HGD HJV HLCS HMBS HOGA1 HPRT1 HPX HSD17B4 ISPD IVD KCNA1 KCNE3 KCTD7 LAMP2 LARGE1 LDHA LFNG LIAS LMBRD1 LPIN1 MAGT1

MAN1B1 MCCC1 MCCC2 MCEE MFSD8 MGAT2 MICU1 MMAA MMAB MMACHC MMADHC MOCOS MOCS2 MOGS MPDU1 MPI MTHFR MTO1 MTR MUT NGLY1 NHLRC1 NSDHL NUS1 OTC OXCT1 PAH PC PCBD1 PCCA PCCB PCK1 PDHA1 PDHB

PDHX PDP1 PEPD PEX1 PEX10 PEX11B PEX12 PEX13 PEX14 PEX16 PEX19 PEX2 PEX26 PEX3 PEX5 PEX6 PEX7 PFKM PGAM2 PGAP2 PGAP3 PGK1 PGM1 PGM3 PHKA1 PHKA2 PHKB PHKG2 PHYH PIGA PIGL PIGM PIGN PIGO

PIGS PIGT PIGV PIGW PMM2 PNP PNPLA2 PNPO POMGNT1 POMGNT2 POMT1 POMT2 PPOX PPT1 PRKAG2 PRKAG3 PRODH PYGL PYGM RBCK1 RFT1 RXYLT1 SCN4A SCP2 SEC23B SI SLC16A1 SLC22A5 SLC25A13 SLC25A15 SLC25A20 SLC2A2 SLC30A2 SLC35A1

SLC35A2 SLC35A3 SLC35C1 SLC35D1 SLC37A4 SLC39A8 SLC40A1 SLC5A1 SLC6A8 SLC7A7 SRD5A3 SSR4 ST3GAL3 ST3GAL5 STT3A STT3B SUGCT TAT TAZ TCN2 TFR2 TMEM165 TMEM199 TPP1 TRAPPC11 TRIM37 TUSC3 UMPS UROD UROS XDH XYLT1 XYLT2


This panel includes the most relevant genes associated with inborn errors of metabolism. It is a large, heterogeneous group of disorders with a global prevalence of 1:600 live-born children. Pathophysiologically, they are characterized by showing one of the following mechanisms: accumulation of a substrate, deficiency of a product, and/or activation of alternative metabolic pathways with subsequent production of toxic metabolites. Overall, these pathologies can be classified into three big groups: defects in the synthesis or catabolism of complex molecules (such as lysosomal and peroxisomal disorders), storage of toxic substances (such as aminoacidopathies, organic acidurias, urea cycle disorders, and sugar intolerances), and energy deficiency metabolic diseases (such as glycogen storage diseases, disorders of gluconeogenesis, congenital lactic acidemias, fatty acid oxidation disorders, and respiratory chain disorders).

inborn errors of metabolism I

29

This panel covers the study of the most relevant genes associated with inborn errors of metabolism due to defects in the synthesis or catabolism of complex molecules. These pathologies, which include storage diseases, are characterized by progressive and permanent clinical features mainly involving the liver, spleen, kidney, nervous system, skeletal muscle, and myocardium.

Among the phenotypes studied by this panel, the following are worth highlighting:

• Lysosomal storage diseases (such as mucopolysaccharidosis, neuronal ceroid lipofuscinosis, Niemann-Pick disease, and Tay-Sachs disease)

• Peroxisomal disorders (such as peroxisome biogenesis disorders, adrenoleukodystrophies, Refsum disease, and rhizomelic chondrodysplasia punctata)

• Congenital disorders of glycosylation

• Metal storage disorders (such as hemochromatosis and Wilson disease)

Disturbances in the synthesis or catabolism of complex molecules

ABCD1 ABCD3 ACOX1 AGA AGK AGPS AGXT ALG1 ALG11 ALG12 ALG13 ALG14 ALG2 ALG3 ALG6 ALG8 ALG9 AMACR ARSA ARSB ARSE ARSG ASAH1 ATP13A2 ATP6AP1 ATP6V0A2 ATP7A

ATP7B B3GALNT2 B3GALT6 B3GAT3 B3GLCT B4GALT1 B4GALT7 BMP2 C1GALT1C1 CAD CAT CCDC115 CHST14 CHST3 CHST6 CHSY1 CLN3 CLN5 CLN6 CLN8 COG1 COG2 COG4 COG5 COG6 COG7 COG8

CP CTNS CTSA CTSD CTSF CTSK DDOST DHDDS DNAJC5 DNM1L DOLK DPAGT1 DPM1 DPM2 DPM3 DYM EBP EXT1 EXT2 FAR1 FKRP FKTN FTH1 FUCA1 FUT8 GAA GALC

GALNS GALNT12 GALNT3 GBA GFPT1 GLA GLB1 GLS GM2A GMPPA GMPPB GNE GNPAT GNPTAB GNPTG GNS GORAB GRHPR GRN GUSB HAMP HEXA HEXB HFE HGSNAT HJV HOGA1

HSD17B4 HYAL1 IDS IDUA ISPD KCTD7 LAMP2 LARGE1 LFNG LIPA MAGT1 MAN1B1 MAN2B1 MANBA MCOLN1 MFSD8 MGAT2 MOGS MPDU1 MPI NAGA NAGLU NEU1 NGLY1 NPC1 NPC2 NSDHL


NUS1 PEX1 PEX11B PEX12 PEX13 PEX14 PEX16 PEX19 PEX2 PEX26 PEX3 PEX5 PEX6 PEX7 PGAP2 PGAP3 PGM1 PGM3 PHYH PIGA PIGL PIGM PIGN PIGO PIGS PIGT PIGV

PIGW PMM2 POMGNT1 POMGNT2 POMT1 POMT2 PPT1 PSAP RFT1 SCP2 SEC23B SGSH SLC17A5 SLC35A1 SLC35A2 SLC35A3 SLC35C1 SLC35D1 SLC39A8 SLC40A1 SMPD1 SRD5A3 SSR4 ST3GAL3 ST3GAL5 STT3A STT3B

SUGCT SUMF1 TFR2 TMEM165 TMEM199 TMEM5 TPP1 TRAPPC11 TRIM37 TUSC3 XYLT1 XYLT2


AGA ARSA ARSB ARSG ASAH1 CLN3 CLN5

CLN6 CLN8 CTNS CTSA CTSD CTSK DNAJC5

FUCA1 GAA GALC GALNS GBA GLA GLB1

GM2A GNE GNPTAB GNPTG GNS GUSB HEXA

HEXB HGSNAT HYAL1 IDS IDUA LAMP2 LIPA

Lysosomal storage diseases panel [51 genes]

MAN2B1 MANBA MCOLN1 MFSD8 NAGA NAGLU NEU1

NPC1 NPC2 PPT1 PSAP SGSH SLC17A5 SMPD1


SUMF1 TPP1

This panel studies the most relevant genes associated with lysosomal storage diseases. These are inherited, mostly autosomal recessive diseases characterized by the inability to degrade macromolecules due to a specific functional defect in lysosomal enzymes; therefore, these macromolecules accumulate inside the lysosome.


• Sphingolipidoses (such as Niemann-Pick disease and Gaucher disease)

• Gangliosidosis (such as Tay-Sachs disease)

• Glycogen storage diseases (such as Pompe disease and Danon disease)

• Glycoproteinoses (such as sialidosis, galactosialidosis, and alpha- and beta-mannosidosis)

• Neuronal ceroid lipofuscinosis

• Mucolipidosis

• Mucopolysaccharidosis

Lysosomal storage diseases

inborn errors of metabolism Iinborn errors of metabolism I

31

ARSB GALNS GLB1

GNS GUSB HGSNAT

HYAL1 IDS IDUA

NAGLU SGSH

Mucopolysaccharidosis panel [11 genes]

ATP13A2 CLN3 CLN5

CLN6 CLN8 CTSD

CTSF DNAJC5 GRN

KCTD7 MFSD8 PPT1

TPP1

Neuronal ceroid lipofuscinosis panel [13 genes]

This panel studies the most relevant genes associated with peroxisomal disorders. These disorders can be classified into peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies.Among the phenotypes studied by this panel, the following are worth highlighting:

• Zellweger spectrum disorders

• Adrenoleukodystrophies

• Refsum disease

• Rhizomelic chondrodysplasia punctata

Peroxisomal disorders

ABCD1 ABCD3 ACOX1 AGK AGPS

AGXT AMACR ARSE CAT DNM1L

DYM EBP FAR1 GNPAT GRHPR

HOGA1 HSD17B4 NSDHL PEX1 PEX10

PEX11B PEX12 PEX13 PEX14 PEX16

Peroxisomal disorders panel [36 genes]

PEX19 PEX2 PEX26 PEX3 PEX5

PEX6 PEX7 PHYH SCP2 SUGCT

TRIM37


Subpanels:

> Mucopolysaccharidosis [11 genes] > Lipofuscinosis neuronal ceroidea [13 genes]


This panel includes the most relevant genes associated with neuronal ceroid lipofuscinosis (NCL). It is a group of neurodegenerative diseases in which ceroid-lipofuscin, an autofluorescent material, accumulates within the neurons of the brain and retina. Ten types are known, and they typically occur at different moments in life: infantile (type I NCL), late infantile (type II NCL), juvenile (type III NCL) and adult (type IV NCL), among others.


This panel includes the most relevant genes associated with the development of mucopolysaccharidosis. This is a heterogeneous group of pathologies characterized by a deficiency in the enzymes in charge of glycosaminoglycans.Among the phenotypes studied by this panel, the following are worth highlighting:

• Mucopolysaccharidosis type I, or Hurler syndrome

• Mucopolysaccharidosis type II, or Hunter syndrome

• Mucopolysaccharidosis type III, or Sanfilippo syndrome

• Mucopolysaccharidosis type IV, or Morquio syndrome

• Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome

• Mucopolysaccharidosis type VII, or Sly syndrome

• Mucopolysaccharidosis type IX, or Natowicz syndrome


33

ALG1 ALG11 ALG12 ALG13 ALG14 ALG2 ALG3 ALG6 ALG8 ALG9 ATP6AP1 ATP6V0A2 B3GALNT2

B3GALT6 B3GAT3 B3GLCT B4GALT1 B4GALT7 C1GALT1C1 CAD CCDC115 CHST14 CHST3 CHST6 CHSY1 COG1

COG2 COG4 COG5 COG6 COG7 COG8 DDOST DHDDS DOLK DPAGT1 DPM1 DPM2 DPM3

EXT1 EXT2 FKRP FKTN FUT8 GALNT12 GALNT3 GFPT1 GLS GMPPA GMPPB GNE GORAB

ISPD LARGE1 LFNG MAGT1 MAN1B1 MGAT2 MOGS MPDU1 MPI NGLY1 NUS1 PGAP2 PGAP3

Congenital disorders of glycosylation panel [102 genes]

PGM1 PGM3 PIGA PIGL PIGM PIGN PIGO PIGS PIGT PIGV PIGW PMM2 POMGNT1

POMGNT2 POMT1 POMT2 RFT1 SEC23B SLC35A1 SLC35A2 SLC35A3 SLC35C1 SLC35D1 SLC39A8 SRD5A3 SSR4


ST3GAL3 ST3GAL5 STT3A STT3B TMEM165 TMEM199 TMEM5 TRAPPC11 TUSC3 XYLT1 XYLT2

This panel studies the most relevant genes associated with congenital disorders of glycosylation. This is a group of pathologies characterized by defects in the activity of enzymes involved in the modification of proteins and other macromolecules through the addition and modification of oligosaccharide side chains.


• Defects of protein N-glycosylation

• Defects of protein O-glycosylation

• Defects of multiple glycosylation

• Defects of sphingolipid glycosylation

• Defects in glycosylphosphatidylinositol anchor

Congenital disorders of glycosylation

This panel studies the most relevant genes associated with metal storage disorders.


• Hemochromatosis

• Wilson's disease

• Aceruloplasminemia

• Menkes disease

Metal storage disorders

ATP7A ATP7B

BMP2 CP

FTH1 HAMP

HFE HJV

SLC40A1 TFR2

Metal storage disorders panel [10 genes]



35

ABAT ACAD8 AGPS ALDH4A ALDH5A1 ALDOB AMT APRT ARG1

ARSE ASPA ASS1 BCKDHA BCKDHB CA5A CBS D2HGDH DBT

DNAJC12 EBP ETHE1 FAH GALE GALK1 GALT GCDH GCSH

GLDC GLUL GNMT GNPAT GSS HAL HGD HPRT1 IVD

LMBRD1 MCCC1 MCCC2 MCEE MMAA MMAB MMACHC MMADHC MOCOS

Toxic matter storage diseases comprehensive panel [68 genes]

MTHFR MTR MUT OTC OXCT1 PAH PCBD1 PCCA PCCB

PEPD PEX7 PNP PNPO PRODH SI SLC25A13 SLC25A15 SLC5A1

SLC7A7 TAT TCN2 UMPS XDH

This panel studies the most relevant genes associated with toxic matter storage diseases. This group of pathologies are characterized by presenting with clinical features typical of intoxication, both acute (vomiting, liver failure, seizures, and coma) and progressive (psychomotor developmental delay and cardiomyopathy). Involvement is mainly neurological, hepatic, and muscular, and onset generally occurs between the neonatal and the school-age period.


• Aminoacidopathies (such as maple syrup urine disease, alkaptonuria, homocystinuria, and phenylketonuria).

• Organic acidemias (such as methylmalonic acidemia and propionic acidemia).

• Urea cycle disorders (such as argininemia and citrullinemia).

• Disorders of purine metabolism (such as Lesch-Nyhan syndrome).

• Sugar intolerances (such as fructosemia, galactosemia, galactokinase deficiency, and galactose-epimerase deficiency).

• Neurotransmitter disorders

Toxic matter storage diseases


This panel studies the most relevant genes associated with energy deficiency metabolic diseases. This group of pathologies usually show multiorgan involvement, with hypotonic seizures, cardiomyopathy, and liver and cardiac failure, triggered by factors such as infections, surgery, prolonged fasting, or other types of stress.


• Glycogen storage disease (such as McArdle disease and Von Glerke disease)

• Disorders of gluconeogenesis

• Congenital lactic acidemias

Energy deficiency metabolic diseases

ACADM ACADS ACADVL ACAT1 AGL ALDH3A2 ALDOA

ALDOB CPT1A CPT2 DLAT ENO3 EPM2A FBP1

FH G6PC GAA GAMT GBE1 GYG1 GYS1

GYS2 HADHA HADHB LAMP2 LDHA LIAS NHLRC1

PC PCK1 PDHA1 PDHB PDHX PDP1 PFKM

Energy deficiency metabolic diseases comprehensive panel [53 genes]

PGAM2 PGK1 PGM1 PHKA1 PHKA2 PHKB PHKG2

PRKAG2 PRKAG3 PYGL PYGM RBCK1 SLC16A1 SLC22A5

SLC25A20 SLC2A2 SLC37A4 SLC6A8



37

AGL ALDOA ALDOB ENO3

EPM2A FBP1 G6PC GAA

GBE1 GYG1 GYS1 GYS2

LAMP2 LDHA NHLRC1 PFKM

PGAM2 PGK1 PGM1 PHKA1

Glycogenosis panel [30 genes]

PHKA2 PHKB PHKG2 PRKAG2

PRKAG3 PYGL PYGM RBCK1

SLC2A2 SLC37A4

This panel studies the most relevant genes associated with glycogenosis. It is a group of hereditary diseases characterized by enzymatic defects that alter glycogenesis or glycogenolysis. Depending on the type, they can lead to inability to convert glycogen into energy and/or to toxic accumulation of glycogen. They primarily affect the liver, skeletal muscle, myocardium, and, occasionally, the nervous system and kidneys. Hypoglycemia, muscle cramps, hypotonia, and exercise intolerance are frequent manifestations.


• Aglycogenosis (glycogen storage disease type 0)

• Von Gierke disease (glycogen storage disease type 1)

• Pompe disease (glycogen storage disease type 2)

• McArdle disease (glycogen storage disease type 5)

• Other types of glycogen storage diseases

Glycogenosis


inborn errors of metabolism I

39

Other genetic tests

other genetic tests I

Gene sequencing

Exome sequencing

SNP array

Variant segregation/Family studies

NextGenDx® massive sequencing (NGS)

MLPA testing

Array CGH

We offer you the possibility of requesting the study of any gene or genes that you consider to be of interest and that are not included in the current portfolio.For more information, contact the sales representative of your area send us an email at [email protected]

Gene sequencing

Individual gene sequencing and interpretation service. Depending on its size and on the regions of interest, we can offer an approach based on Sanger sequencing or on NGS (enrichment using amplicons or hybridization probes). The NGS-based approach allows detecting copy number variations (CNVs).

NextGenDx® massive sequencing (NGS)

Next Generation Sequencing (NGS), or massive sequencing, is a term used to describe a group of newly developed technologies able to perform massive DNA sequencing. This means that millions of small DNA fragments can be sequenced at once, generating a vast amount of data. These data can add up to gigabytes of information, equivalent to 1,000 millions of DNA base pairs. In comparison, formerly used methods could only sequence one DNA fragment at a time, generating between 500 and 1,000 DNA base pairs in a single reaction.

NextGenDx® is indicated when a specific group of genes needs to be analyzed at the highest levels of diagnostic accuracy. It is aimed at:

• Monogenic diseases or diseases associated with a small number or large genes.

• Multigenic or genetically heterogeneous diseases with complex differential diagnosis.

Exome sequencing

NGS service based on sequencing the coding portion of the human genome. It is a versatile tool that enables the simultaneous testing of a large amount of genes, and it is particularly useful in those cases where clinical presentation does not allow selecting a specific clinical panel or in pathologies with a very wide range of candidate genes, e.g. epilepsy. The exome service allows for TARGETED (predefined) testing of a group of candidate genes or for CLINICAL (open) analysis, where an ad hoc test is performed based on the clinical features of each particular case. The most complex cases may benefit from TRIO- or FAMILY-BASED exome testing, which jointly analyze the exomes of several family members, taking into account the status of each studied individual (affected or healthy) and the suspected inheritance pattern.

41

MLPA testing

Semiquantitative technique that is widely applied in molecular genetic laboratories and that allows diagnosing patho-logies caused by copy number variations and, in some cases, by alterations in DNA methylation. A wide variety of commercial kits are available to test individual genes, gene panels related to specific pathologies, or large chromo-somal regions involved in microdeletion/microduplication syndromes. HIC offers MLPA services based on MRC-Ho-lland kits.

SNP array

They include more than 290 microdeletion/microduplication syndromes. Array analysis allows detecting copy number gains or losses throughout the whole genetic material of the patient. Within the field of cardiology, it is considered a first-line test for patients with congenital heart disease associated with other malformations, particularly intellectual disability, autism spectrum disorders, and/or multiple congenital malforma-tions. SNP array testing can detect copy number variations (CNVs) throughout the whole genetic material and allows confirming or ruling out microdeletion/microduplication syndromes, such as deletion 22q11 (velocardiofacial syndrome), deletion 7q11 (Williams syndrome), etc.

Indication for genetic testing. It is considered a first-line test in postnatal analysis for multiple non-specific congenital abnormalities and/or mental retardation/intellectual disability.

Among its advantages are the possibility of testing DNA from virtually any tissue, including non-cultured tissue; the detection of citogenetic abnormalities that cannot be detected by conventional tests; the identification of breakage points in chromosomal rearrangements, and the detection of loss of heterozygosity (SNP array only).

However, this technique also has some limitations. One of them is that it cannot detect balanced chromosomal rearran-gements (balanced translocations or inversions); however, it can determine whether rearrangements show losses or gains at breakage points. Likewise, it cannot detect low-level mosaicism, triploidy and other levels of polyploidy, or some aneuploidies such as XYY. CNVs from genomic regions are not covered by the platform. Moreover, the level of detection depends on study density. It does not allow detecting point mutations or gene expression, nor does it allow for methylation analysis. It also shows some limitations in the case of trisomies secondary to translocations (trisomies 13 and 21).

Array CGH

It is also known as molecular karyotyping, and its main advantage over classic karyotyping is its high sensitivity, which allows detecting structural variants that go unnoticed in conventional karyotyping. CGH array technology allows detecting losses and gains of genetic material and unbalanced rearrangements throughout the whole genome of an individual.

Postnatal CGX 108K is specifically designed for genetic diagnosis. Its mean resolution is 100 kb over the whole genome, and high resolution is 20 kb for regions of interest of the genome (regions with direct association between copy number variations and a described pathology or syndrome).

Array 37K is specifically designed for prenatal diagnosis and allows detecting genetic and chromosomal alterations with a single test. Its resolution is 10 times greater than that of conventional karyotyping and 50 times greater in critical regions for the main syndromes. Without substantially decreasing resolution in regions of interest, CGX 37K shows low coverage levels in the rest of the genome in order to minimize diagnostic uncertainty.

Variant segregation/Family studies

Sanger sequencing studies on carriers of variants that have been previously described in the family.

43

Sequencing panels Turnaround time: 5 weeks

Lipid metabolism disorders:S-202009816 Lipid metabolism disorders comprehensive panel [78 genes + hypolipidemic agent pharmacoge-

netics + genetic risk for coronary disease]Familial hypercholesterolemia:

S-201805878 Comprehensive panel [13 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

S-201805070 Basic plus panel [5 genes + hypolipidemic agent pharmacogenetics + genetic risk for coronary disease]

S-201601178 Basic panel [6 genes]S-201805879 Primary/polygenic hypertriglyceridemia and familial combined hyperlipidemia [47 genes]S-202009808 Lipodystrophies [15 genes]S-202007872 Hypolipidemias [14 genes]

Endocrine disorders:S-202009815 Endocrine disorders comprehensive panel [435 genes]S-202009806 Thyroid disorders [36 genes]

S-202009818 Disorders of sex development, alterations in the hypothalamic-pituitary-gonadal axis, and infertility [125 genes]S-202008730 Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. CYP21A2 (Sanger and MLPA)S-202009805 Adrenal diseases [53 genes]S-202009802 Monogenic diabetes, hyperinsulinemias, and monogenic hypoglycemias [81 genes]S-202009801 Maturity-onset diabetes of the young (MODY) [15 genes]S-202009811 Pancreatitis and pancreatic insufficiency [15 genes]S-202009817 Pituitary disorders and short stature [88 genes]S-202009819 Phosphocalcic metabolism disorders [37 genes]S-202009804 Multi-endocrine disorders [6 genes]S-202009810 Monogenic obesity [70 genes]

Inborn errors of metabolism:S-202009713 Inborn errors of metabolism comprehensive panel [305 genes]S-202009814 Disturbances in the synthesis or catabolism of complex molecules comprehensive panel [202 S-202009803 Lysosomal storage diseases [51 genes]S-202008340 Mucopolysaccharidosis [11 genes]S-202009809 Neuronal ceroid lipofuscinosis [13 genes]S-202009820 Peroxisomal disorders [36 genes]S-202009800 Congenital disorders of glycosylation [102 genes]S-202009821 Metal storage disorders [10 genes]S-202009813 Toxic matter storage diseases comprehensive panel [68 genes]S-202009812 Energy deficiency metabolic diseases comprehensive panel [53 genes]S-202009807 Glycogenosis [30 genes]

Reference Test

List of services I

Other genetic tests

Consult the price and turnaround time with the team at [email protected]

We offer you the possibility of requesting the study of any gene or genes that you consider to be of interest and that are not included in the current portfolio.

For more information, contact the sales representative of your area send us an email at [email protected]

45

PRE-TEST AND POST-TEST COUNSELLING

Our studies include the possibility of pre-test and post-test counselling

For more information, please contact your sales representative

47

The quality assurance and management system of the Health in Code group combines the most rigorous management system standards (ISO 9001:2015) with excellence in performance and technical competence of a leading clinical diagnostic laboratory (authorized health center) (ISO 15189:2013 and CLIA-88) and efficient and respectful environmental management (ISO 14001:2015).

In addition, at Health in Code, we are members of the EMQN network (European Molecular Genetics Quality Network, United Kingdom) and GenQA Genomics Quality Assessment, United Kingdom), participating periodically in rigorous intercomparison tests (EQA Schemes) and obtaining highly satisfactory results that support our quality in both technical execution and clinical interpretation.

Our quality assurance has been recognized and positively evaluated by the College of American Pathologists (CAP, USA) for the detection of variants using NGS sequencing (CAP # 8280234-01).

The Health in Code services are pursuant to Spanish law on the protection of personal data (Organic Law 15/1999, of December 13, on the Protection of Personal Data, LOPD) and, therefore, to European regulations on data protection, in particular to the provisions of Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016.

Our genetic diagnostic laboratories are accredited to the UNE-EN ISO 15189 standard by the Spanish national accreditation entity (ENAC) and the International Laboratory Accreditation Cooperation (ILAC). This accredi-tation represents the highest quality standard applicable to clinical laboratories at the international level.

The scope of UNE-EN ISO 15189 of Health in Code laboratories combines state-of-the-art massive parallel sequencing (custom NGS panels, targeted and whole exome sequencing) with reference techniques (gold standard) in genetics—Sanger sequencing, MLPA, dPCR, and array CGH—constituting a pioneering laboratory in obtaining a flexible scope that can be extended to all its genetic diagnostic services.

It should be noted that our laboratory's analytical developments, such testing for copy number variation (CNV), or structural variants, using a NGS depth coverage technique and mtDNA sequencing through the amplification of the complete mitochondrial genome and NGS, have been accredited to the ISO 15189 standard among first in Spain.

To achieve this, we have employed our custom-developed software for genetic diagnosis and analysis certified to the ISO 13485:2016 standard that also has the CE-IVD mark.

Additionally, Health in Code has received the prestigious CLIA certification (Clinical Laboratory Improvement Amendments) granted by the Centers for Medicare & Medical Services (CMS) of the US Federal Government, which authorizes it to perform high-complexity genetic testing (CLIA ID number 99D2153048), being one of the select group of 66 clinical laboratories worldwide that can process samples from the US outside of their territories.

Accreditations and quality assurance

+34 881 600 003 I [email protected] I www.healthincode.com For more information, please contact your sales representative

Documents

ATHERO-ENDOCRINE-METABOLIC DISEASES