Edition of 10 October 2018

A brief communication was published in Annals of Neurology reported of two female patients with de novo variants in KCNT2, a member (with KCNT1) of the SDLO2 family of NA+-dependent (K+) channel genes. This new KCNT2-related disorder shares similar phenotypic features previously known for KCNT1-related disorders, presenting a West syndrome followed by Lennox-Gastaut syndrome or with developmental and epileptic encephalopaty and migrating focal seizures.

The authors of this study report a unique de novo TP53 germline variants found in two individuals with an inherited bone-marrow-failure syndrome accompanied by hypogammaglobulinemia, growth retardation and microcephaly mimicking Diamond-Blackfan anemia and dyskeratosis congenita. The variants caused a truncation of the protein, that when expressed in zebrafish or human-induced pluripotent stem cells, impaired erythrocyte production.

The study describes 11 patients with de novo heterozygous missense mutations in SYT1, coding for a mediator of fast, synchronous, calcium-dependent neurotransmitter release. These patients exhibited phenotypic features including infantile hypotonia, congenital ophtalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics included sleep disturbance, and episodic agitation. There was an absence of epileptic seizures and normal orbitofrontal head circumference in these patients. Authors added that variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

Three unrelated individuals harbouring a de novo heterozygous copy number loss of CCNK and one individual harbouring a de novo nonsynonymous variant in CCNK shared a common phenotype of developmental delay and intellectual disability, language defects and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge, and narrow jaw. In vivo studies in the zebrafish supported the idea of a role of CCNK in neurodevelopment.

Three consanguineous families exhibited biallelic truncating mutations in CTNNA2, encoding αN-catenin, linked to a distinct recessive form of pachygyria. In vitro studies identified CTNNA2 as having a role in ARP2/3 complex regulation, an actin nucleating protein.