Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data?

BACKGROUND: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries. METHODS: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria. RESULTS: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting. CONCLUSION: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high-throughput sequencing data, especially in a clinical context given the implications.

Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience.

OBJECTIVE: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. STUDY DESIGN: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. RESULTS: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). CONCLUSION: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease.

Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status.