De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism.

Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy.

The first case of deafness-dystonia syndrome due to compound heterozygous variants in .

We report the second known family affected by deafness-dystonia syndrome associated with loss of function of . Our patient is compound heterozygous for pathogenic variants, while affected siblings in the first report were homozygous. This case provides evidence that this novel genetic disorder is associated with autosomal recessive inheritance.

A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy.

The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders.

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.

Experience in the use of clobazam in the treatment of Lennox-Gastaut syndrome.

Clobazam is a 1,5-benzodiazepine used successfully worldwide since the 1970s as an anxiolytic and antiepileptic drug. Since its recent Food and Drug Administration (FDA) approval in the United States in 2011 as adjunctive treatment for Lennox-Gastaut syndrome, it has continued to show sustained efficacy and a better safety and tolerability profile compared with other benzodiazepines. The two randomized, controlled studies that led to the US FDA approval, as well as the follow-up multicenter, open-label study of clobazam, showed ≥50% seizure reduction for more than 50% of Lennox-Gastaut syndrome patients, while none of the other FDA-approved treatments for LGS have demonstrated efficacy rates better than 50%.