1. A recessive variant in SIM2 in a child with complex craniofacial anomalies and global developmental delay
- Author
-
Alya A. Al-Kurbi, Sahar Isa Da'as, Waleed Aamer, Navaneethakrishnan Krishnamoorthy, Ilaria Poggiolini, Doua Abdelrahman, Najwa Elbashir, Ammira Al-Shabeeb Akil, Graeme E. Glass, and Khalid A. Fakhro
- Subjects
Craniofacial Abnormalities ,Phenotype ,Intellectual Disability ,Homozygote ,Genetics ,Basic Helix-Loop-Helix Transcription Factors ,Microcephaly ,Animals ,Humans ,General Medicine ,Down Syndrome ,Genetics (clinical) ,Zebrafish - 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 AG, 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 SIM2
- Published
- 2021