• neurodevelopmental disorder with speech impairment and dysmorphic facies

This report describes neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID); NEDSID exhibits autosomal dominant inheritance. The phenotypic features and severity of this disorder are variable and may include susceptibility to schizophrenia. The human gene implicated in this disease is SETD1A, which encodes a component of a histone methyltransferase (HMT) complex that methylates histone H3 at Lys4 (H3K4); trimethylation of H3K4 is observed near the transcription start sites of most active genes. There is a single orthologous gene in Drosophila, Set1, for which multiple genetic reagents have been generated including loss-of-function and missense mutations, RNAi targeting constructs, and overexpression constructs. Dmel\Set1 is also orthologous to the human gene SETD1B.

The human SETD1A gene has not been introduced into flies.

Loss-of-function mutations of Dmel\Set1 are lethal. Targeted knockdown of Set1, effected by RNAi, in terminally differentiated postmitotic neurons of the mushroom body of the brain results in short- and long-term memory deficits; no morphological abnormalities are observed. These findings add support to the idea that H3K4 methylation plays a conserved role in regulating the function of adult neurons post-development.

Other genes involved in H3K4 methylation have been implicated in human diseases that impact neural function; see the Human Disease Model reports 'Kleefstra syndrome 2' (FBhh0000717) and 'intellectual disability, X-linked, syndromic, Claes-Jensen type' (FBhh0000849) for cases that have been modeled in flies.

[updated Sep. 2021 by FlyBase; FBrf0222196]