Biallelic loss of EMC10 leads to mild to severe intellectual disability.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.

Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested.

PURPOSE: Reanalysis of exome sequencing data when results are negative may yield additional diagnoses. We sought to estimate the contribution of clinical geneticists to the interpretation of sequencing data of their patients. METHODS: The cohort included 84 probands attending a tertiary genetics institute (2015-2018) with a nondiagnostic result on clinical exome sequencing performed in one of five external laboratories. The raw data were uploaded to the Emedgene bioinformatics and interpretation platform for reanalysis by a team of two clinical geneticists, the geneticist directly involved in the patient's care, and a bioinformatician. RESULTS: In ten probands (11.9%), a new definitive diagnosis was reached based on genes that were known to be associated with the phenotype at the time the original report was issued. The main reasons for a negative exome result were incorrect interpretation of the clinical context and absence of OMIM entry. Pathogenic variants in genes with previously unknown gene-disease associations were discovered to be causative in three probands. In total, new diagnoses were established in 13/84 individuals (15.5%). CONCLUSION: Direct access to complete clinical data and shortening of time to including gene-phenotype associations in databases can assist the analytics team and reduce the need for additional unnecessary tests.

Undetected sex chromosome aneuploidy by chromosomal microarray.

We report on a case of a female fetus found to be mosaic for Turner syndrome (45,X) and trisomy X (47,XXX). Chromosomal microarray analysis (CMA) failed to detect the aneuploidy because of a normal average dosage of the X chromosome. This case represents an unusual instance in which CMA may not detect chromosomal aberrations. Such a possibility should be taken into consideration in similar cases where CMA is used in a clinical setting.