Extending the spectrum of CLRN1‐ and ABCA4‐associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing

Abstract

Background Inherited retinal dystrophies (IRDs) are characterized by extreme genetic and clinical heterogeneity. There are many genes that are known to cause IRD which makes the identification of the underlying genetic causes quite challenging. And in view of the emergence of therapeutic options, it is essential to combine molecular and clinical data to correctly diagnose IRD patients. In this study, we aimed to identify the disease‐causing variants (DCVs) in four consanguineous Jordanian families with IRDs and describe genotype–phenotype correlations. Methods Exome sequencing (ES) was employed on the proband patients of each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. Simulation analysis was done on one novel CLRN1 variant to characterize its effect on mRNA processing. Clinical evaluation included history, slit‐lamp biomicroscopy, and indirect ophthalmoscopy. Results We identified two novel variants in CLRN1 [(c.433+1G>A) and (c.323T>C, p.Leu108Pro)], and two recurrent variants in ABCA4 [(c.1648G>A, p.Gly550Arg) and (c.5460+1G>A)]. Two families with the same DCV were found to have different phenotypes and another family was shown to have sector RP. Moreover, simulation analysis for the CLRN1 splice donor variant (c.433+1G>A) showed that the variant might affect mRNA processing resulting in the formation of an abnormal receptor. Also, a family that was previously diagnosed with nonsyndromic RP was found to have Usher syndrome based on their genetic assessment and audiometry. Conclusion Our findings extend the spectrum of CLRN1‐ and ABCA4‐associated IRDs and describe new phenotypes for these genes. We also highlighted the importance of combining molecular and clinical data to correctly diagnose IRDs and the utility of simulation analysis to predict the effect of splice donor variants on protein formation and function.

Unique Variant Spectrum in a Jordanian Cohort with Inherited Retinal Dystrophies

“…In 35 families (64%), the inheritance pattern was autosomal-recessive, whereas the probands in 20 families (35%) were from sporadic cases. Among autosomal-recessive IRD families, 11 were previously reported and described [ 19 , 23 , 24 ]. Age of patients ranged from 4 to 64 years with a mean of 31 years.…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…genes) [92]; celiac disease (CPED1 gene) [93]; hereditary spherocytosis type 3 (SPTA1 gene) [89]; developmental delay, cerebellar hypoplasia, and myoclonic seizures (KCNMA1 gene) [74]; Cenani-Lenz syndrome (APC gene) [74]; Sjogren-Larsson syndrome (ELOVL4 gene) [74]; autism spectrum disorder (multigene) [94]; congenital heart disease (PRKD1 gene) [95]; ciliopathies [96]; Parkinsonism (PLA2G6 gene) [97]; retinal dystrophies (CLRN1, ABCA4, CERKL, AGBL5, CDH16, and DNAJC17 genes) [98][99][100]; Pediatric Asthma [101]; cardiovascular genetic diseases (LDLR gene) [102]; enteroendocrine dysfunction (PCSK1) [103]; tricho-hepato-enteric syndrome (TTC37 and SKIV2L) [104]; Wolcott-Rallison syndrome (EIF2AK3) [105], Fanconi-Bickel syndrome (SLC2A2) [105] and Alström syndrome (Exon 19 Skipping in ALMS1 Gene) [106,107]; using whole exome or whole genome analysis revealed disease markers in Saudi population. Families with autosomal recessive retinal dystrophies from various ethnicity including Saudis were analysed for candidate genes using WES, 45 unique deleterious variants including 18 novel variants observed [108].…”

“…Variants in the Mendeliome in Saudi ancestry – APC-related Cenani-Lenz syndrome, Steel syndrome, syndromic cataract, oral-facial-digital syndrome, CHARGE-like presentation, epileptic encephalopathy, Ehlers-Danlos-like syndrome, and congenital hydrocephalus – were reported either with compatible phenotypes (homozygous variant in 30 genes) or phenotypes different from the original reports (homozygous mutations in 18 candidate genes) [ 79 ]. Studies on systemic juvenile idiopathic arthritis ( LACC1 gene) [ 80 , 81 ]; recurrent pregnancy loss ( ASIC5 gene) [ 82 ]; tricho-hepato-enteric syndrome ( SKIV2L and TTC37 genes) [ 83 ]; STING-associated vasculopathy of infantile-onset ( STING1 gene) [ 84 ]; multiple congenital anomaly syndrome ( SMG9 gene) [ 85 ]; diabetic retinopathy ( NME3 , LOC728699 , and FASTK genes) [ 86 ]; congenital neutropenia with inflammatory bowel disease ( G6PC3 gene) [ 87 ]; skeletal dysplasia ( XYLT1 ) [ 88 , 89 ]; Wolf–Hirschhorn syndrome ( WHSC1 gene) [ 90 ]; lymphatic dysplasia with nonimmune hydrops fetalis ( PIEZO1 ) [ 89 ]; Cohen syndrome ( VPS13B gene) [ 91 ]; severe combined immunodeficiency disease ( AK2 , JAK3 , and MTHFD1 genes) [ 92 ]; celiac disease ( CPED1 gene) [ 93 ]; hereditary spherocytosis type 3 ( SPTA1 gene) [ 89 ]; developmental delay, cerebellar hypoplasia, and myoclonic seizures ( KCNMA1 gene) [ 74 ]; Cenani-Lenz syndrome ( APC gene) [ 74 ]; Sjogren-Larsson syndrome ( ELOVL4 gene) [ 74 ]; autism spectrum disorder (multigene) [ 94 ]; congenital heart disease ( PRKD1 gene) [ 95 ]; ciliopathies [ 96 ]; Parkinsonism ( PLA2G6 gene) [ 97 ]; retinal dystrophies ( CLRN1 , ABCA4 , CERKL , AGBL5 , CDH16 , and DNAJC17 genes) [ 98 – 100 ]; pediatric asthma [ 101 ]; cardiovascular genetic diseases ( LDLR gene) [ 102 ]; enteroendocrine dysfunction ( PCSK1 ) [ 103 ]; tricho-hepato-enteric syndrome ( TTC37 and SKIV2L ) [ 104 ]; Wolcott–Rallison syndrome ( EIF2AK3 ) [ 105 ], Fanconi–Bickel syndrome ( SLC2A2 ) [ ...…”