Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants

Abstract

Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.

Fig. 1

Reported variants in the SAND domain of DEAF1. Multispecies alignment of the SAND domain in the DEAF1 protein isoforms of human, rat, mouse, zebrafish and drosophila (major protein isoforms displayed). Arrows depict DEAF1-SAND domain residues with reported variants, including our novel variant in gray highlight. All variants are reported as heterozygous de novo, except for R226 W which was reported to occur homozygous in two independent families. Amino acids with similar properties are marked in italic underlined print, and dissimilar amino acids are marked in bold underlined

Fig. 2

Expression of the paternal derived de novo NDN variant in case M2922 with a maternal imprinted NDN allele. a Phasing the de novo NDN variant through inspection of the BAM sequencing files. Screenshot from genome viewer with alignment sorted by allele at c.838 showing nearby maternally inherited SNP rs2192206 (‘c.858 T allele’) in distinct sequence reads than the de novo variant (‘c.838 C allele’) suggesting the mutation occurred on the paternal allele. b Sanger confirmation of the c.838G > C NDN variant and the nearby synonymous SNP (rs2192206): c.858C > T, and sequencing of fibroblast cDNA confirms de novo inheritance and monoallelic cDNA expression of the variant. This confirms that the de novo variant in the proband occurs on the paternally derived allele and imprinting silences the maternally derived reference allele

Fig. 3

Integration into the gene-association network for SMS-like disorders. Gene-association network from the STRING database demonstrates a network significantly enriched for gene associations between the genes identified in the SMS-like cohort (DEAF1, IQSEC2, MAPK8IP3, NDN, KAT5, and BAP1) and the RAI1-associated disease network (KMT2D (mapped to MLL2 by STRING), ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ) as previously reported (Loviglio et al. 2016)