PUBLICATION
A recessive variant in SIM2 in a child with complex craniofacial anomalies and global developmental delay
- Authors
- Al-Kurbi, A.A., Da'as, S.I., Aamer, W., Krishnamoorthy, N., Poggiolini, I., Abdelrahman, D., Elbashir, N., Al-Shabeeb Akil, A., Glass, G.E., Fakhro, K.A.
- ID
- ZDB-PUB-220220-7
- Date
- 2022
- Source
- European Journal of Medical Genetics 65(4): 104455 (Journal)
- Registered Authors
- Da'as, Sahar
- Keywords
- Craniosynostosis, Developmental delay, Facial dysmorphism, Intellectual disability, Whole-genome sequencing, Zebrafish model
- MeSH Terms
-
- Animals
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Craniofacial Abnormalities*/genetics
- Craniofacial Abnormalities*/pathology
- Down Syndrome*
- Homozygote
- Humans
- Intellectual Disability*/genetics
- Intellectual Disability*/pathology
- Microcephaly*/genetics
- Phenotype
- Zebrafish/genetics
- PubMed
- 35182808 Full text @ Eur. J. Med. Genet.
Citation
Al-Kurbi, A.A., Da'as, S.I., Aamer, W., Krishnamoorthy, N., Poggiolini, I., Abdelrahman, D., Elbashir, N., Al-Shabeeb Akil, A., Glass, G.E., Fakhro, K.A. (2022) A recessive variant in SIM2 in a child with complex craniofacial anomalies and global developmental delay. European Journal of Medical Genetics. 65(4):104455.
Abstract
Rare deletions and duplications on the long arm of Chromosome 21 have previously been reported in many patients with craniofacial and developmental phenotypes. However, this Down Syndrome Critical Region (DSCR) contains multiple genes, making identifying a single causative gene difficult. Here, we report a case of a boy with bicoronal craniosynostosis, facial dysmorphism, developmental delay, and intellectual impairment who was found by whole genome sequencing to have a homozygous missense mutation in the Single-Minded Homolog 2 (SIM2) gene (c.461 A > G, p.Tyr154Cys) within the DSCR. SIM2 encodes an essential bHLH and PAS domain transcription factor expressed during fetal brain development and acts as a master regulator of neurogenesis. This variant is globally very rare, segregates in the family, and is predicted to be highly deleterious by in silico analysis, 3D molecular modeling of protein structure, and functional analysis of zebrafish models. Zebrafish expressing the human SIM2p.Y154C variant displayed a progressed microcephaly-like phenotype and head shape abnormalities. When combined with careful phenotyping of the patient vis-à-vis previously reported cases harboring structural variants in this critical 21q22 region, the data support a pathogenic role of SIM2 in this complex syndrome and demonstrates the utility of next-generation sequencing in prioritizing genes in contiguous deletions/duplications syndromes and diagnosing microarray-negative patients in the craniofacial clinic.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping