Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

Abstract

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…7,10 This prompted us to examine the yield of this approach for dysmorphology syndromes in the same setting, i.e., multiplex consanguineous families. Another reason for limiting our study to multiplex families is that the presence of more than one affected individual with the same apparently novel phenotype facilitates the recognition of the core phenotypic features of the syndrome, notwithstanding the known phenomenon of clinical variability.…”

“…Close examination of the known disease genes within the two critical intervals highlighted C21orf2, an established disease gene for cone-rod dystrophy. 7 Interestingly, one of the two C21orf2-linked cone-rod dystrophy families that we had originally described 7 was found on careful examination to display short stature and narrow chest whereas the other was completely nonsyndromic. Thus, C21orf2 appears to cause both syndromic and nonsyndromic cone-rod dysfunction.…”

“…For example, we have published the identification of several novel candidate genes in the setting of retinal dystrophy and primordial dwarfism, and some of these genes have since been independently verified by others. [7][8][9] Recently, we published the identification of 33 novel candidate genes for various neurocognitive phenotypes, and at least 6 of these were independently found to be mutated by other investigators in the few months since the article appeared online (unpublished data). 10 However, we are not aware of any similar effort to accelerate the discovery of novel candidate genes specifically in the setting of dysmorphology syndromes.…”

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

“…[3][4][5] Notably, this approach has been used for the development of next-generation molecular diagnosis of hereditary eye disorders. [6][7][8] Abu-Safieh and colleagues 6 designed an autozygome-guided screening panel in which they were able to successfully identify IRD in patients with six novel candidate genes. In another study, 163 known IRD genes were screened for by exome sequencing in 179 patients with Leber congenital amaurosis and juvenile RP, identifying a genetic predisposition in 40.2% (72/179) of the cases.…”

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

“…Determination of the entire set of autozygous intervals per genome (autozygome) and autozygosity mapping were carried out as described previously. 16,17 Briefly, we used algorithms (AutoSNPa and HomozygosityMapper) that consider regions of homozygosity (ROH) >2 Mb in size as surrogates of autozygosity.…”