Confirmation of the Role ofDHX38in the Etiology of Early-Onset Retinitis Pigmentosa

Abstract

PurposeRetinitis pigmentosa (RP) is a genetically heterogeneous trait with autosomal-recessive (ar) inheritance underlying 50% of genetic disease cases. Sixty-one arRP genes have been identified, and recently, DHX38 has been reported as a potential candidate gene for arRP with only a single family reported with a variant of unknown significance. We identified a missense variant in DHX38 that co-segregates with the arRP phenotype in two Pakistani families confirming the involvement of DHX38 in the etiology of early-onset RP.MethodsExome sequencing was performed using two DNA samples from affected members of Pakistani families (MA88 and MA157) with early onset arRP. Sanger sequencing of DNA samples from all family members confirmed the segregation of candidate variant within both families.ResultsA novel missense DHX38 variant c.971G>A; p.(Arg324Gln) was identified which segregates with the arRP phenotype and yielded a logarithm of the odds (LOD) score of 5.0 and 4.3 for families MA88 and MA157, respectively. This variant is predicted to be conserved and deleterious by several bioinformatics tools.ConclusionsWe identified a second deleterious DHX38 variant that segregates with arRP in two families, providing additional evidence that DHX38 is involved in RP etiology. DHX38 encodes for pre-mRNA splicing factor PRP16, which is important in catalyzing pre-mRNA splicing.

An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data

“…DHX38 had been first associated to IRD (OMIM:618220) with homozygous missense variant c.995G>A:p.(Gly332Asp) found in four affected sibs from a consanguineous Pakistani family with early-onset retinitis pigmentosa and macular coloboma [80] and, more recently, has been confirmed to cause early-onset retinitis pigmentosa in two consanguineous Pakistani families with early-onset retinitis pigmentosa [81] with same homozygous missense variant c.971G>A:p.(Arg324Gln) also seen in patient P43 (Leber congenital amaurosis; rank 7) from the IRD dataset in this analysis. Exomiser did not identify any known gene-phenotype annotations in human disease (Table S4) as the current version of the Exomiser phenotype database does not contain yet the OMIM:618220 phenotypic annotation for DHX38.…”

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

“…Two missense variants with a MAF of 0.0016% and 0.0012% were identified in known disease genes (S1 Table): c.889C>T/p. (Arg297Cys) in DHX38 (MIM: 605584) in which two other amino acid substitutions have been reported in individuals with autosomal recessively inherited early-onset retinitis pigmentosa (MIM: 268000) [52,53] and c.5083C>A/p. (Pro1695Thr) in MYO15A (MIM: 602666) in which biallelic mutations cause autosomal-recessive, nonsyndromic deafness (DFNB3, MIM: 600316) [54,55].…”

“…The DHX38 variant p.(Arg297Cys) was predicted to be possibly damaging by two of three programs (S1 Table). In individuals with a pathogenic DHX38 variant, blindness is caused by retinitis pigmentosa and occurred between 7 and 8 years of age, and the majority of affected individuals developed cataract by the age of 19 years [52]. In contrast, the diagnosis of blindness in patients 1 and 2 described here was established within the first year of their life, and ophthalmologic examination at age 15 years and 22 years, respectively, did not reveal any signs of cataract and/or retinitis pigmentosa.…”

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

“…10,11 Furthermore, a third member of this paralogous gene family, DHX38 (MIM: 605584), was reported recently as a candidate gene in three unrelated families with early-onset autosomal-recessive retinitis pigmentosa (RP84 [MIM: 618220]) in association with homozygous missense DHX38 variants. 14,15 In light of these findings and the correlation between gene paralogs and human disease phenotypes, we hypothesized that variant alleles in other members of the DExD/H-box RNA helicase gene family might also underlie neurodevelopmental disease traits, and we investigated their potential role in trait manifestations of human disease biology. Through the Baylor Hopkins Center for Mendelian Genomics (BHCMG) and collaborations facilitated by GeneMatcher, 16,17 we provide evidence supporting that DHX37 (MIM: 617362), DHX16 (MIM: 603405), DDX54 (MIM: 611665), and DHX34 (MIM: 615475) are neurodevelopmental genes ( Figure 1).…”