Journal Article

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

Introne, Wendy J., Smith, Ann C. M., Billington, Charles, Berger, Seth I., Fischer, Roxanne, Blancato, Jan K., Malicdan, May Christine, Gahl, William A., Mullikin, James C., Vilboux, Thierry, Ciccone, Carla, Simon, Karen L., Huizing, Marjan, Gropman, Andrea

2017

Overview

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.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Adolescent / Adult / Amino Acid Sequence / Analysis / Animals / Biomedical and Life Sciences / Biomedicine / Child, Preschool / Cohort Studies / Exome / Female / Gene Function / Genes / Genetic aspects / Genetic testing / Genomes / Guanine Nucleotide Exchange Factors - genetics / Human Genetics / Humans / Intellectual disabilities / Male / Metabolic Diseases / Molecular Medicine / Mutation / Nuclear Proteins - genetics / Original Investigation / Research centers / Sequence Homology, Amino Acid / Sleep disorders / Smith-Magenis Syndrome - genetics / SMS (Short messaging service) / Transcription Factors - genetics / Tumor Suppressor Proteins - genetics