Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees

Abstract

BackgroundRetinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES).MethodsTwenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification.ResultsAll patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology.ConclusionsOur study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1522-7) contains supplementary material, which is available to authorized users.

Non-photoreceptor Expression of Tulp1 May Contribute to Extensive Retinal Degeneration in Tulp1-/- Mice

“…A bioinformatic analysis of IRD genes suggests widespread expression of many other IRD genes in both inner and outer retinal cell types during early development. These findings raise the possibility that gene therapies targeting TULP1 (Widgren et al, 2016;Chen et al, 2018) (Jacobson et al, 2014;Avela et al, 2019) and other similarly expressed IRD genes, may possibly need to restore expression of these genes in both photoreceptor and non-photoreceptor cells. Furthermore, early postnatal expression of these genes highlights a potential hurdle for future treatments of some IRDs.…”

Usher syndrome and Nebulin‐associated myopathy in a single patient due to variants in MYO7A and NEB

“…Genome-wide technologies enable the identification of potentially causal variants in human disease and establish coherent genotype-phenotype associations, particularly in conditions with complex clinical presentation and genetic heterogeneity, [1][2][3][4] with a thorough interpretation of causality due to incomplete penetrance, mosaicism, or variable disease expression. 1,[4][5][6][7][8][9][10] Homozygosity mapping proved invaluable in identifying variants in recessive Mendelian diseases, particularly in consanguineous families. 11,12 Although rare, phenotypic heterogeneity of typical Mendelian segregating disorders, caused by combined effects in several genes, has been previously described.…”

Recent Developments on the major genes involved in retinitis pigmentosa

“…2,[5][6][7] The age of onset varies among different patients, but usually it ranges from early childhood to mid-adulthood. 7,8 It may affect the clinical manifestations as early RP onset appears mostly with rapid progress, while other patients remain asymptomatic until the fifth decade of life. 7 The first symptom of RP is usually nyctalopia (night blindness) and difficulties in dark to light and light to dark adaptation.…”