Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Abstract

Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.

Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease

“…Over the past decade, this technology has revolutionised the diagnosis of genetically heterogeneous conditions like IRD [8]. Importantly, there is a lack of studies that have examined the yield of genetic testing in syndromic IRD in general as most reports focus on either isolated IRD, or on specific conditions such as Usher syndrome [7][8][9][10][11][12]. A panel-based NGS test for IRD genes was designed by the Genomic Diagnostics Laboratory within Manchester Centre for Genomic Medicine (MCGM) in 2012 to genetically test for a custom group of genes known to be causative for both isolated and syndromic IRD conditions.…”

High Prevalence Mutations in ALMS1 in Spanish Alström Patients

“…In our cohort, we analysed 13 patients with causal ALMS mutations. Most of them have been described previously 4 . We have detected two mutations with high prevalence within our cohort.…”

“…Alström Syndrome (ALMS; OMIM #203800) is considered an ultra-rare disorder, with an estimated prevalence lower than 1 in 1,000,000 in European-descent populations and over 800 cases described worldwide, of which 13 patients have been diagnosed in Spain [1][2][3][4] . As in the case of other rare syndromes, consanguineous and/or geographically isolated populations refer higher frequency values [5][6][7] .…”

“…Main clinical characteristics are described in Table 2. Mutations in these families were described elsewhere 1 and, as part of the Spanish ciliopathy cohort they have been studied by our group 3,4 .…”

A very early diagnosis of Alstrӧm syndrome by next generation sequencing

“…More than 200 variants in ALMS1 have been described, mainly involving frameshift or nonsense variants that introduce premature stop codons [29]. Most of the ALMS1 variants detected are clustered in exons 8 (49% of all known variants), 10 and 16 [29][30][31][32][33], although other variants have been reported in exon 5 [34][35][36] and others in intronic regions [29,33,37,38].…”