High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

Abstract

Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

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

“…21 However, we note here that we cannot exclude the possibility of dual diagnosis and the presence of more than one underlying causal mutation in consanguineous pedigrees as described recently. 22 Second, a distinct dysmorphology profile is present in each of the study families, and this will be much more likely to facilitate "matchmaking" as compared with some of the nonspecific phenotypes reported by Bloss et al (e.g., developmental delay and muscle atrophy).…”

Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

“…A Clinical exome sequencing (CES) study in Middle Eastern patients with suspected Mendelian disorders showed that MANF was one of novel candidate disease genes [32]. MANF gene is mutated in intron regions in a 22-year-old woman presented with T2DM, obesity and other disease phenotypes.…”

Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data

“…Its efficacy is especially augmented over gene-by-gene Sanger sequencing and the candidate gene approach7 in genetically heterogeneous diseases such as retinitis pigmentosa (RP) and congenital hearing loss. However, WES analysis fails to detect mutations in many families with hereditary diseases and an average detection rate of only 50–60% has been reported in various conditions 8. Moreover, WES analysis is not efficient for the identification of large deletions as a function of its design, mainly since the traditional WES analysis schemes are designed to identify single-nucleotide variations or those involving a few bases only.…”