A recessive variant in SIM2 in a child with complex craniofacial anomalies and global developmental delay

Al-Kurbi, Alya; Da’as, Sahar; Aamer, Waleed; Krishnamoorthy, Navaneethakrishnan; Poggiolini, Ilaria; Abdelrahman, Doua; Elbashir, Najwa; Akil, Ammira Al‐Shabeeb; Glass, Graeme E.; Fakhro, Khalid

doi:10.1016/j.ejmg.2022.104455

Cited by 2 publications

(2 citation statements)

References 21 publications

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“…Mouse models have established that deletion of the Sim2 gene produces a variety of developmental phenotypes; however, the extent to which SIM2 gene variants cause or contribute to human pathologies remains undetermined. Recently a study proposed a homozygous SIM2 variant (p.Tyr154Cys) as the cause of the clinical presentation in a child with craniofacial abnormalities, developmental delay and intellectual disability [ 25 ]. Understanding the molecular basis of how non-synonymous nucleotide variants can alter the activity of SIM2 will not only provide a greater understanding of the way SIM2 functions as a transcription factor but could also highlight the possibility of these variants causing or contributing to human disease.…”

Section: Discussionmentioning

confidence: 99%

Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes

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Rossi

McDougal

et al. 2022

Biochemical Journal

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Single-Minded 2 (SIM2) is a neuron enriched basic Helix-Loop-Helix/PER-ARNT-SIM (bHLH/PAS) transcription factor essential for mammalian survival. SIM2 is located within the Down Syndrome Critical Region (DSCR) of chromosome 21, and manipulation in mouse models suggests Sim2 may play a role in brain development and function. During screening of a clinical exome sequencing database, nine SIM2 non-synonymous mutations were found which were subsequently investigated for impaired function using cell-based reporter gene assays. A number of these human variants attenuated abilities to activate transcription and were further characterized to determine the mechanisms underpinning their deficiencies. These included impaired partner protein dimerization, reduced DNA binding and reduced expression and nuclear localization. This study highlighted several SIM2 variants found in patients with disabilities and validated a candidate set as potentially contributing to pathology.

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Section: Discussionmentioning

confidence: 99%

Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes

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Rossi

McDougal

et al. 2022

Biochemical Journal

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“…We first applied our optimized laboratory processing pipelines that look for recessive mutations (Al-Kurbi et al 2022) and structural variants (E Aliyev, A Visconti, N Syed, et al, unpubl.), but we did not find any candidate variants that could be linked to the presented disease phenotype. We then used a combinatorial approach for de novo mutation calling that leverages three separate underlying approaches to identify 92 high genotype quality de novo variants.…”

Section: Genomic Analysesmentioning

confidence: 99%

A de novo start-loss in EFTUD2 associated with mandibulofacial dysostosis with microcephaly: case report

Kohailan

Al-Saei

Padmajeya

et al. 2022

Cold Spring Harb Mol Case Stud

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Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental delay, craniofacial malformations such as malar and mandibular hypoplasia, and ear anomalies. Here, we report a 4.5-yr-old female patient with symptoms fitting MFDM. Using whole-genome sequencing, we identified a de novo start-codon loss (c.3G > T) in the EFTUD2. We examined EFTUD2 expression in the patient by RNA sequencing and observed a notable functional consequence of the variant on gene expression in the patient. We identified a novel variant for the development of MFDM in humans. To the best of our knowledge, this is the first report of a start-codon loss in EFTUD2 associated with MFDM.

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A recessive variant in SIM2 in a child with complex craniofacial anomalies and global developmental delay

Cited by 2 publications

References 21 publications

Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes

Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes

A de novo start-loss in EFTUD2 associated with mandibulofacial dysostosis with microcephaly: case report

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