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.

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.

De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures.

The voltage-gated Kv10.1 potassium channel, also known as ether-a-go-go-related gene 1, encoded by KCNH1 (potassium voltage-gated channel, subfamily H (eag related), member 1) is predominantly expressed in the central nervous system. Recently, de novo missense KCNH1 mutations have been identified in six patients with Zimmermann-Laband syndrome and in four patients with Temple-Baraitser syndrome.

Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.

Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children.