Edition of 31 January 2019

An research letter published in the American Journal of Medical Genetics expands the TRMT1-linked phenotype to which no detailed clinical or radiological data were available. The four further affected individuals were in two pedigrees with healthy, consanguineous parents of Pakistani descent. Non‐syndromical microcephaly was diagnosed at birth, and later mild to moderate intellectual disability became apparent.

Two siblings were identified presenting neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord. Exome sequencing revealed an heterozygous frameshift mutation in ZIC1.

A study published in The American Journal of Human Genetics identified six persons from three families presenting intellectual disability with speech delay, short stature, microcephaly, and aggressive behaviour. Three homozygous protein truncating variants in PUS7 were found in these individuals. The gene encodes the RNA-independent pseudouridylate synthase 7. Knockout of pus7 in Drosophila melanogaster resulted in a number of behavioural defects, suggesting that RNA pseudouridylation by PUS7 is important for proper neuronal development and function.

The American Journal of Genetics recently published an article identifying two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. The pathogenic gene encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Zebrafish models showcased clinically relevant phenotypes with renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression.

Researchers identified four patients with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. The disorder was associated with de novo heterozygous, gain-of-function variants in ODC1, encoding the rate-limiting enzyme in endogenous polyamine synthesis.