De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth.

CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.

Settlement of the classification of Svistella Gorochov and Paratrigonidium Brunner von Wattenwyl using morphology and molecular techniques, with the description of a new species from Yunnan, China (Orthoptera: Trigonidiidae: Trigonidiinae).

It is difficult to distinguish the genera Svistella and Paratrigonidium on the basis of morphology. Gorochov postulated that Svistella spp. possess the following identification characters: posterior lateral lobes of epiphallus long and narrow at apex, guide rod elongate, attachment plate of the spermatophore consisting of three sclerites (a narrow middle sclerite bearing no protruding structure, and a pair of lateral ones extending to the sides). These features have not been extensively evaluated. In this study, the COI gene was sequenced and was used as a DNA marker to distinguish two genera. The results showed that each genus formed a monophyly, respectively. One new species, Svistella fuscoterminata sp. nov., was found in Yunnan, China. Although its genitalia were similar to that of Paratrigonidium spp., the molecular result supported the new species belonging to Svistella. The specimens are deposited in East China Normal University, Biology of History Museum (ECNU) and Shanghai Entomological Museum (SEM).