Table 1.
Rare HI variants identified in the Roma families
| Family | Gene | Phenotype | Known/novel Gene | Genotype | Segr info | Transcript | cDNA | Protein | Known/novel HI variant | GERP + + RS | CADD | rs_ID | gnomAD All MAF | gnomAD MAF NFE | gnomAD MAF SAS | ACMGa |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 6001 | GJB2 | HI | Known | Hom | Recessive | NM_004004.5 | c.35delG | p.(Gly12fs) | Known | NA | NA | rs80338939 | 6.19 × 10−3 | 9.58 × 10−3 | 8.17 × 10−4 | Pathogenic |
| 6003 | MYH9 | HI | Known | Het | Dominant | NM_002473.5 | c.3682G>A | p.(Glu1228Lys) | Novel | 4.98 | 31 | rs746956415 | 1.19 × 10−5 | 1.76 × 10−5 | 0 | VUS |
| 6004 | GJB2 | HI | Known | Hom | Recessive | NM_004004.5 | c.35delG | p.(Gly12fs) | Known | NA | NA | rs80338939 | 6.19 × 10−3 | 9.58 × 10−3 | 8.17 × 10−4 | Pathogenic |
| 6005 | MANBA | HI, ID, RI, ADHD | Known syndromic | Hom | Recessive | NM_005908.3 | c.2158-2A>G | Splicingb | Known | 5.17 | 23.4 | rs772852668 | 2.39 × 10−5 | 1.76 × 10−5 | 0 | Pathogenic |
| 6006 | USH2A | HIc | Known | Comp Het | Recessive | NM_206933.2 | c.908G>A | p.(Arg303His) | Known | 4.93 | 34 | rs371777049 | 3.90 × 10−5 | 6.23 × 10−5 | 0 | Pathogenic |
| 6006 | USH2A | HIc | Known | Comp Het | Recessive | NM_206933.2 | c.2522C>A | p.(Ser841Tyr) | Known | 6.03 | 24.5 | rs111033282 | 6.06 × 10−3 | 8.92 × 10−3 | 1.11 × 10−3 | VUS |
| 6007 | GJB2 | HI | Known | Hom | Recessive | NM_004004.5 | c.71G>A | p.(Trp24*) | Known | 5.21 | 36 | rs104894396 | 5.22 × 10−4 | 6.26 × 10−5 | 4.38 × 10−3 | Pathogenic |
| 6008 | MYO7A | HI | Known | Het | Dominantd | NM_000260.3 | c.4107G>T | p.(Gln1369His) | Novel | 4.69 | 24.6 | . | 0 | 0 | 0 | VUS |
| 6009 | USH1G | HIe | Known | Comp Het | Recessive | NM_173477.4 | c.854dupG | p.(Ala286fs) | Novel | NA | NA | . | 0 | 0 | 0 | Pathogenic |
| 6009 | USH1G | HIe | Known | Comp Het | Recessive | NM_173477.4 | c.314C>T | p.(Ala105Val) | Novel | 2.8 | 24.9 | . | 0 | 0 | 0 | Likely pathogenic |
| 6010 | GJB2 | HI | Known | Hom | Recessive | NM_004004.5 | c.35delG | p.(Gly12fs) | Known | NA | NA | rs80338939 | 6.19 × 10−3 | 9.58 × 10−3 | 8.17 × 10−4 | Pathogenic |
| 6011 | GJB2 | HI | Known | Hom | Recessive | NM_004004.5 | c.35delG | p.(Gly12fs) | Known | NA | NA | rs80338939 | 6.19 × 10−3 | 9.58 × 10−3 | 8.17 × 10−4 | Pathogenic |
| 6012 | PLS1 | HI | Novel, causes HI in mice | Het | Dominant | NM_002670.2 | c.1087C>T | p.(Leu363Phe) | Novel | 5.73 | 29.9 | . | 0 | 0 | 0 | VUS |
Abbreviations are as follows:
Genotypes: Hom: Homozygous; Comp Het: Compound heterozygous; Het: Heterozygous
Phenotype codes: ADHD: attention-deficit/hyperactivity disorder; HI: hearing impairment; ID: intellectual disability; RI: respiratory inflammation
Population codes: NFE: Non-Finnish European; SAS: South Asian
Scores and frequencies: ACMG: American College of Medical Genetics and Genomics classification of variants; CADD, Combined Annotation Dependent Depletion v1.3; gnomAD, Genome Aggregation Database v.2.1; NA, not available; MAF, minor allele frequency; VUS: variant of unknown significance
aMore details can be found in Supplementary Table S2
bNG_012804.1:g.130948 A > G. The dbscSNV ADA and RF scores are 1 and 0.932, respectively
cAffected and unaffected siblings both are affected with hypermetropia
dPotentially autosomal recessive
eAffected siblings also suffer from polycystic ovarium syndrome and hypothyreosis