Table 1. Recessive Variants Identified in 10 Candidate Genes.
| Gene | Mode of inheritance | Functional impact | Transcript variant | Protein variant | Inheritance | Genotype in brother (II.1) | Genotype in sister (II.2) | gnomAD* MAF (%) | dbSNP ID |
|---|---|---|---|---|---|---|---|---|---|
| HSPG2 | Cmpd Het | missense | c.2074G > A; c.2077G > A | p.V692M; p.V693M | Maternal | WT | WT | 0.288 | 143669458 |
| missense | c.326G > A | p.R109Q | Paternal | Het | Het | 0 | 773796176 | ||
| promoter | c.-227C > A | Paternal | WT | WT | 1.392 | 566166086 | |||
| SLC9A1 | Cmpd Het | promoter | c.-906T > C | Paternal | Het | Het | 1.227 | 114101904 | |
| promoter | c.-947T > G | Maternal | WT | WT | 27.175 | 11588974 | |||
| promoter | c.-1085A > G | Paternal | Het | Het | 0.841 | 116299278 | |||
| ENCODE TFBS | c.-1138C > T | Paternal | Het | Het | 0.93 | 75089536 | |||
| promoter | c.-1311G > A | Paternal | Het | Het | 0.93 | 77414471 | |||
| APOB | Cmpd Het | missense | c.13441G > A | p.A4481T | Maternal | WT | Het | 2.475 | 1801695 |
| missense | c.751G > A | p.A251T | Paternal | Het | WT | 0.071 | 61741625 | ||
| LRP2 | Cmpd Het | missense | c.9613A > G | p.N3205D | Maternal | WT | WT | 0.407 | 35734447 |
| missense | c.170C > T | p.A57V | Paternal | WT | WT | 0.032 | 115350461 | ||
| SDHD | Cmpd Het | promoter | c.-815G > C; c.129+547C > G | Maternal | Het | WT | 0.573 | 117661257 | |
| ENCODE TFBS | c.-205G > A; c.66C > T | p.A22A | Paternal | WT | WT | 0.241 | 61734353 | ||
| missense | c.34G > A; c.-173C > T | p.G12S | Maternal | Het | WT | 0.729 | 34677591 | ||
| PRTG | Cmpd Het | microRNA Binding Site | c.*3501T > G | Paternal | Het | WT | 0.739 | 77181316 | |
| microRNA Binding Site | c.*2678A > G | Maternal | WT | Het | 0.019 | 756136447 | |||
| HN1 | Cmpd Het | ENCODE TFBS | c.56+617C > T; c.-903C > T; c.-178+617C > T; c.-590C > T | Maternal | Het | WT | 3.764 | 117213586 | |
| promoter | c.-1748A > C; c.-719A > C; c.-486A > C | Paternal | WT | Het | 0.816 | 73995795 | |||
| SIK1 | Hom Rec | missense | c.2087C > T | p.P696L | Maternal and Paternal | WT | Het | 1256991707 | |
| ELF4 | X-Linked | missense | c.1144G > A | p.V382I | Maternal | WT | Het | 0.025 | 148953158 |
| HS6ST2 | X-Linked | missense | c.948–40041G > A; c.1046G > A | p.R349Q | Maternal | WT | Het | 0.146 | 201239951 |
Cmpd Het, compound heterozygous; Het, heterozygous; Hom Rec, homozygous recessive; MAF, minor allele frequency; WT, wild- type.
*At study initiation the ESP database was used to set the 3% allele frequency filter. Updated frequencies are shown based on the newer gnomAD database curation which would now eliminate SLC9A1 and HN1 as candidate genes.