Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the mitochondriopathy of the homologous null mouse.

Mitochondriopathies are a group of clinically heterogeneous genetic diseases caused by defects in mitochondrial metabolism, bioenergetic efficiency, and/or signaling functions. The large majority of proteins involved in mitochondrial function are encoded by nuclear genes, with many yet to be associated with human disease. We performed exome sequencing on a young girl with a suspected mitochondrial myopathy that manifested as progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis.

Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown.

15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features.

Deletion within the proximal region of chromosome 15q11.2 between breakpoints 1 and 2 (BP1-BP2) has been proposed to be a risk factor for intellectual disability, seizure, and schizophrenia. However, the clinical significance of its reciprocal duplication is not clearly defined yet.

A 15q13.3 homozygous microdeletion associated with a severe neurodevelopmental disorder suggests putative functions of the TRPM1, CHRNA7, and other homozygously deleted genes.

We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe visual impairment, hypotonia, profound intellectual disability, and refractory epilepsy. The homozygous deletion of the genes within this deleted region provides a useful insight into the pathogenesis of the observed clinical phenotype.