Nature Biotechnology: doi:10.1038/nbt · PDF fileNumbers on axes are quantitative scores defined in Supplementary Table 1. A smaller number indicates a severe score. The radar plot

Supplementary Figure 1

Workflow of the retrospective Resilience Project to build allele and gene panels and interrogate existing sequencing data

Nature Biotechnology: doi:10.1038/nbt.3514


Distribution of mutation types in the Resilience Project core allele panel (CAP)



Comprehensive annotation of 674 mutations in the Core Allele Panel (CAP).

From the outside to inside layers the annotations include disease category (outermost layer, one color per gene); average read depth per allele in a representative full exome sequencing study (red barchart: SWE-SCZ; N=5092; Agilent SureSelect Human All Exon v2, covering 33Mb); relative number of known disease-causing variants in CAP per gene (light blue) and gene name; name of the mutation;


number of samples screened in our study (blue bar chart); age of onset, penetrance, severity, and evidence (orange/red heat map, with red or 1 depicting earliest onset variants, fully penetrant, most severe, and the most reliable evidence; consult Supplementary Table 7 for more details). A cross-section with respect to the CFTR p.F508del mutation is highlighted to illustrate each of these different layer. The average read depth at this site in the exome sequencing study SWE-SCZ study was 68 (red bar chart). The minimum read depth across the CFTR exons was 21, the maximum 279, with one intronic variant not covered in any of the 5,092 samples. This p.F508del variant is marked as "mostly early age of onset (<18y)"; complete penetrance with a known exception; and severe disease manifestation plus variable expressivity (all three in dark orange). The evidence comes from a large cohort and is therefore marked by a red bar.



Number of samples analyzed for the alleles in the core allele panel (CAP)

Since ESP6500 provides only variant calls, we define coverage of a core allele by ESP6500 based on the existence of any variant within a -/+100bp window around each core allele.



Radar plots showing clinical manifestations of 8 disorders for the 13 identified resilient candidate individuals

The axes of radar plot are indicating quantitative scores used for clinical annotation for alleles, with lower score (category 1) outsideand higher score (category 4) inside. A larger radar map suggests a more severe phenotype.



Disease selection criteria plot

Numbers on axes are quantitative scores defined in Supplementary Table 1. A smaller number indicates a severe score. The radar plot is showing disease selection criteria in the current study: a disease with complete or near complete penetrance, early onset (symptom developed younger than 18y) and significantly reduced mobility or increased mortality.



Overlaps of current gene and allele panels with published carrier screening panels


Supplementary Table 4: DHCR7 variants in two resilient candidates from UK10K that are annotated by ClinVar, HGMD, OMIM, and/or SwissVar. The first variant is contained in our core allele panel and was used to identify the two candidates. Both candidates exhibit the same five additional annotated variants. In total, the two individuals had 15 and 18 DHCR7 variants, respectively.

Variant Genotype in resilient

candidate 1

Genotype in resilient

candidate 2

Sources Clinical significance

Annotated phenotype

11:71146886C>G (rs138659167)

1/1 1/1 HGMD; ClinVar

DM; pathogenic Smith-Lemli-Opitz syndrome

11:71155171C>T (rs1044482)

1/1 1/1 ClinVar Benign AllHighlyPenetrant

11:71155153A>G (rs1790334)


11:71146577G>A (rs909217)


11:71152461A>G (rs949177)


11:71146691A>G (rs760241)



Supplementary Table 5: Possible resilient candidates with less stringent filtering criteria

Phenotype Gene Mutation Panel number of homozygotes

source comments

cDNA Protein

Incomplete penetrance (milder or asymptomatic homo individuals have been reported)

Biotinidase deficiency BTD c.1368A>C p.Q456H CAP 1 BGI most common allele, disease treatable Autoimmune lymphoproliferative syndrome

CASP10 c.1216A>T p.Ile406Leu EAP 1 CHOP recurrent, functional study evidence

Achromatopsia CNGB3 c.1148del1 p.T383Ifs*13 CAP 1+2 ESP;23andMe most common mutation, accounts for >70% alleles,variable phenotype

Primary congenital glaucoma CYP1B1 c.1103G>A p.R368H EAP 10 23andMe high carrier frequency in Ashkenazi Jews, disease treatable, multiple asymptomatic homozygotes have been seen, probably incomplete penetrance

Primary Congenital Glaucoma CYP1B1 c.685G>A p.E229K EAP 1 ESP high frequency in Caucasian, disease treatable

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia

CYP21A2 c.293-13C>G

EAP 8 UK10K;BGI common allele, homozygous patients were seen in NC form (mild, late-onset)

Maple Syrup Urine Disease Type III / Lipoamide Dehydrogenase Deficiency (E3)

DLD c.685G>T p.G229C EAP 1+1 ESP;23andMe Ashkenazi Jewish founder mutation, homozygotes have variable phenotype, can be asymptomatic

Isovaleric acidaemia IVD c.941C>T p.A314V EAP 1 23andMe homozygotes or compound heterozygotes could be mild or asymptomatic

Gaucher disease GBA c.[1226A>G];[1297G>T]

p.[N409S];[V433L]

EAP 1 TCGA two mutations are possibly in cis

Homocystinuria CBS c.833T>C p.I278T EAP 1 ESP most common mutant allele, homozygotes may be asymptomatic

Methylmalonic Acidemia MCEE c.427C>T p.R143C EAP 4 ESP;Colon,FINN;UK10K

variable clinical manifestation

Total: 33 More likely to be polymorphism

Familial hemophagocytic lymphohistiocytosis

UNC13D c.2782C>T p.R928C EAP 4+1+2 FINN;Colon;ESP controversial, SIFT tolerated, Polyphen deleterious, found in patients that carry 3 variants

Steroid-Resistant Nephrotic Syndrome

NPHS2 c.686G>A p.R229Q EAP 2+5+6+4 TGP, ESP, Colon/CFR, TCGA, FINN;UK10K;BGI

Inconsistency in literature reports, as VUS

Myopathy, dilatative MYF6 c.269C>A p.A90D EAP 5 CHOP;BGI no detailed literature report


21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia, Classic

CYP21A2 c.719T>A p.M240K EAP 11 1KG;23ANDME pseudogene-derived mutation, single mutation seem to be normal, combinations w. other mutations are associated with severe phenotypes

X-Linked Adrenoleukodystrophy

ABCD1 c.707G>A p.Arg236His EAP 1+1 CHOP;BGI single case, reported to be together with another recurrent mutation in a patient, maybe polymorphism

Osteogenesis imperfecta COL1A1 c.3897C>G p.C1299W EAP 1 CHOP dominant mutation, reported to segerate with mild phenotype in a multi-generation family

Total: 43 Not sufficient evidence

Argininosuccinate Lyase Deficiency

ASL c.392C>T p.Thr131Met EAP 1 CHOP reported to be compound heterozygous in a patient with almost no enzyme activity, not sufficient evidence

Marinesco-Sjogren syndrome SIL1 c.274C>T p.R92W EAP 2 CHOP;BGI reported homozygous in single family Congenital Myasthenic Syndrome

CHRNE c.872C>T p.Ala291Val EAP 4 TCGA only one report, compound heterzygous with another common mut

Total: 7 Phenotype can be affected by environmental factors

MCADD ACADM c.985A>G p.K329E EAP 10+2+1 23andMe;UK10K;MSSM SWE-SCZ

severe mutation, phenotype can be affected by environmental factors to be asymptomatic or late-onset

Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD c.634A>G p.Met212Val EAP 5 CHOP phenotype affected by evironment, pateint may be asymptomatic

Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD c.844G>C p.Asp282His EAP 1 BGI mild phenotype/asymptomatic

PKU PAH c.1208C>T p.A403V CAP 1 23andMe milder mutation, disease is treatable and can be picked up by newborn screening

PKU PAH c.1241A>G p.Y414C EAP 5 23andMe milder mutation, high residual enzymatic activity

PKU PAH c.838G>A p.E280K CAP 3 23andMe homozygosity is associated with variant PKU, disease is treatable and can be picked up by newborn screening

Total: 28


Supplementary Table 6: Disease categorization codes

Disease category code Disease category

CD cardiac

CU cutaneous (dermatology)

DF deafness

DV developmental

ED endocrine

GE gastroenterologic

HM hematologic

HP hepatic

IM immunodeficiency

MB metabolic

NM neuromuscular

NU neurological

OC ocular

OT other

RN renal

RP respiratory

SK skeletal


Supplementary Table 7: Categories and quantitative scores used to annotate phenotypes and observed alleles

Score Description Penetrance

1 Complete (>99%) 2 Complete with known exception (>95%) 3 Unknown (>90%) 4 Highly (>80%) 5 incomplete

Age of Onset 1 Congenital or very early (<2 y) 2 mostly early (<18 y) 3 early (<18y) plus variable 4 Late (>18 y) 5 unknown

Severity 1 severe, significantly reduced mobility or increased mortality in early life 2 Severe plus variable expressivity 3 obvious but not life-threatening 4 mild, not affect life quality and span, not obvious 5 unknown

Evidence 1 large cohort, including locus-specific mutation database 2 multiple families/patients (including reviews and carrier screening panels) 3 single family/patient 4 functional study 5 unknown

Variant Category 1 Missense 2 Nonsense 3 Splicing 4 in-frame insertion/deletion 5 frameshift insertion/deletion


Documents

Nature Biotechnology: doi:10.1038/nbt · PDF fileNumbers on axes are quantitative scores defined in Supplementary Table 1. A smaller number indicates a severe score. The radar plot