By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.

Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1,2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1,2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r2=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.

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Summary Purpose KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation. Methods A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high‐resolution melting (HRM) analysis or whole‐exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation. Key Findings A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression‐burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate‐to‐profound intellectual disability was found in all except one patient who died at 3 months. Significance De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression‐burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.

AADC deficiency causes severe motor and intellectual disability as a result of reduced catecholamine levels. Kojima et al. report beneficial effects of gene therapy in six patients with heterogeneous genetic backgrounds. Gene delivery into putamen improved motor function in all patients, plus verbal and cognitive skills in one moderate-phenotype patient.