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Keywords: Chromosomal deletions; Copy number/structural variation; Exome sequencing; Genotype-phenotype correlations; Intellectual and developmental disability

J. Murry 1; I. Mannucci 2; H.-J. Kreienkamp 2; D. Lessel 2; P.B. Shieh 3; T. Althoff 4; J. Abramson 4; A. Slavotinek 5; J.A. Martinez-Agosto 6,7; S.F. Nelson 1,3,6,7; F. Quintero-Rivera 1,7

1) Dept. of Pathology and Lab. Med., UCLA Center for Health Sciences, David Geffen School of Medicine, University of California Los Angeles; 2) Institute for Human Genetics. University Medical Center Hamburg-Eppendorf. Hamburg, Germany; 3) Dept. of Neurology, David Geffen School of Medicine, University of California Los Angeles; 4) Dept. of Physiology, David Geffen School of Medicine, University of California Los Angeles; 5) Dept. of Pediatrics, University of California San Francisco; 6) Dept. of Human Genetics, University of California Los Angeles; 7) UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California Los Angeles

The RNA helicase DHX30, of the DExH-box protein family, is predicted to mediate ATP dependent unwinding of RNA secondary structure and is highly expressed during brain neurogenesis. Five unique de novo missense DHX30 variants have been described in patients with Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language (NEDMIAL syndrome, MIM: 617804), conferring impaired ATPase activity or RNA binding, implicating the helicase domain of its encoded protein, suggesting that accumulated mutant protein leads to a global decrease in protein synthesis (Lessel et al 2017). However, the consequences of DHX30 deletion in humans are unknown. Chromosomal microarray analysis detected a de novo 1.1 Mb loss of 3p21.31 in a 3-year-old with hypotonia, developmental delay (DD), and speech delay with motor impairment, experiencing difficulty climbing stairs, and falling frequently. Brain MRI detected Chiari malformation and hypomyelination. Of the deleted genes, DHX30 was associated with NEDMIAL, whose phenotype partially overlapped with our patient’s, and was predicted to be dosage-sensitive. This is the first report of full gene deletion and a milder presentation compared to others with missense variants in DHX30.

In parallel, clinical exome sequencing found novel missense DHX30 variants in two patients with intellectual disability, DD and NEDMIAL spectrum. Both, a de novo p.R782Q and p.T739A localize to the helicase domain. 3D-Protein modeling for both supports helicase localization, predicting ATPase deficiency. Functional analysis of the missense mutations will be presented. Helicase-inactivating missense variants may exert a spectrum of dominant negative phenotypes and could suggest that over-expression of the mutant helicase protein potentially interferes with normal RNA metabolism, and may be one way in which dominant-negative missense variants may lead to a greater defect compared to that of a heterozygous deletion allele with ≤50% protein activity. We report 1) the first complete null DHX30 allele conferring a milder phenotype than the severity associated with missense SNVs in patients who are non-verbal have no independent walking, and present with delayed myelination with cerebellar or cerebral atrophy, and dilated ventricles; 2) Two novel missense variants associated with NEDMIAL. All three patients add to the limited phenotypes of patients with NEDMIAL and spectrum, guiding clinical interpretation for these and other novel DHX30 variants.