Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience

Abstract

BackgroundClinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically‐oriented data sharing.MethodsThis is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first‐tier) test from April 2014 to December 2016 for various clinical indications.ResultsThe CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex‐WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001).ConclusionMiddle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.

When to think outside the autozygome: Best practices for exome sequencing in “consanguineous” families

“…The proportion of solved families in our cohort (46.2%) is somewhat higher than the average diagnostic yield in unselected cohorts reported by large clinical diagnostic laboratories, but is in keeping with yields reported in highly consanguineous populations . Our high diagnostic yield likely relates to the intentional focus on consanguineous families, the highly selected nature of our patients based on clinical phenotyping, and the research‐oriented approach to analysis, which resulted in multiple diagnoses in novel genes.…”

“…The diagnostic yield of ES in consanguineous cohorts has been well studied, but much of the published literature has emerged from regions where first and second cousin marriages are routine and consanguinity is common. In such populations, the singleton approach to ES has been used with success reflected in high diagnostic rates . In Canada, consanguinity is not as prevalent, yet the population is extremely heterogeneous.…”

Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1

“…Biallelic pathogenic variants in one nuclear‐encoded protein, mitochondrial calcium uptake 1 (MICU1) have recently been described to cause myopathy with extrapyramidal signs (MPXPS). MPXPS has been reported in 41 cases (Table S1) and presents with myopathy, learning disability, and extrapyramidal movement disorder . The MICU1 protein regulates calcium influx into mitochondria through interaction with the mitochondrial calcium uniporter (MCU).…”

Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility

“…Al-Dewik et al, established the genetic diagnosis in 48.3% patients with rare genetic disorders (246/509). Diagnostic yield was higher in consanguineous families (52.4 vs. 39.5%) 19 . Al-Shamsi et al reported 50% ES diagnostic yield among 85 patients suspected to have inborn errors of metabolism 20 .…”