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

被引:2
作者
Al-Kurbi, Alya A. [1 ,2 ]
Aamer, Waleed [2 ]
Krishnamoorthy, Navaneethakrishnan [2 ]
Poggiolini, Ilaria [2 ]
Abdelrahman, Doua [2 ]
Elbashir, Najwa [2 ]
Glass, Graeme E. [3 ]
Fakhro, Khalid A. [1 ,2 ,4 ,5 ]
Daas, Sahar Isa
Al-Shabeeb Akil, Ammira
机构
[1] Hamad Bin Khalifa Univ, Coll Hlth & Life Sci, 34110, Doha, Qatar
[2] Sidra Med, Dept Human Genet, 26999, Doha, Qatar
[3] Sidra Med, Div Plast & Craniofacial Surg, 26999, Doha, Qatar
[4] Weill Cornell Med Coll, Dept Genet Med, 24144, Doha, Qatar
[5] Sidra Med, Dept Human Genet, Doha, Qatar
关键词
Craniosynostosis; Facial dysmorphism; Developmental delay; Intellectual disability; Whole-genome sequencing; Zebrafish model; MOLECULAR CYTOGENETIC CHARACTERIZATION; SYNDROME CRITICAL REGION; SINGLE-MINDED GENE; EXPRESSION; DROSOPHILA; DELETION; CHROMOSOME-21; PATHOGENESIS; DUPLICATION; FEATURES;
D O I
10.1016/j.ejmg.2022.104455
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 SIM2(p.Y154C) variant displayed a progressed microcephaly-like phenotype and head shape abnormalities. When combined with careful phenotyping of the patient vis-`a-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.
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相关论文
共 20 条
  • [1] Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies
    Chatterjee, Arpita
    Dutta, Samikshan
    Mukherjee, Sanjit
    Mukherjee, Nupur
    Dutta, Avirup
    Mukherjee, Ashis
    Sinha, Swagata
    Panda, Chinmay Kumar
    Chaudhuri, Keya
    Roy, Ananda L.
    Mukhopadhyay, Kanchan
    [J]. BMC MEDICAL GENETICS, 2013, 14
  • [2] A de novo duplication of chromosome 21q22.11 → qter associated with Down syndrome: Prenatal diagnosis, molecular cytogenetic characterization and fetal ultrasound findings
    Chen, Chih-Ping
    Huang, Hsu-Kuang
    Ling, Pei-Ying
    Su, Yi-Ning
    Chen, Ming
    Tsai, Fuu-Jen
    Wu, Pei-Chen
    Chern, Schu-Rern
    Chen, Yu-Ting
    Lee, Chen-Chi
    Wang, Wayseen
    [J]. TAIWANESE JOURNAL OF OBSTETRICS & GYNECOLOGY, 2011, 50 (04): : 492 - 498
  • [3] SINGLE-MINDED AND DOWN-SYNDROME
    CHEN, H
    CHRAST, R
    ROSSIER, C
    GOS, A
    ANTONARAKIS, SE
    KUDOH, J
    YAMAKI, A
    SHINDOH, N
    MAEDA, H
    MINOSHIMA, S
    SHIMIZU, N
    [J]. NATURE GENETICS, 1995, 10 (01) : 9 - 10
  • [4] Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of down syndrome
    Fan, CM
    Kuwana, E
    Bulfone, A
    Fletcher, CF
    Copeland, NG
    Jenkins, NA
    Crews, S
    Martinez, S
    Puelles, L
    Rubenstein, JLR
    TessierLavigne, M
    [J]. MOLECULAR AND CELLULAR NEUROSCIENCE, 1996, 7 (01) : 1 - 16
  • [5] Microdeletion of the Down Syndrome Critical Region at 21q22
    Fujita, Hideki
    Torii, Chiharu
    Kosaki, Rika
    Yamaguchi, Shinya
    Kudoh, Jun
    Hayashi, Kumiko
    Takahashi, Takao
    Kosaki, Kenjiro
    [J]. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2010, 152A (04) : 950 - 953
  • [6] Hussein I.R., 2015, Journal of Molecular Biomarkers Diagnosis, V6, P1, DOI DOI 10.4172/2157-7099.1000377
  • [7] THE DROSOPHILA SINGLE-MINDED GENE ENCODES A HELIX-LOOP-HELIX PROTEIN THAT ACTS AS A MASTER REGULATOR OF CNS MIDLINE DEVELOPMENT
    NAMBU, JR
    LEWIS, JO
    WHARTON, KA
    CREWS, ST
    [J]. CELL, 1991, 67 (06) : 1157 - 1167
  • [8] THE SINGLE-MINDED GENE OF DROSOPHILA IS REQUIRED FOR THE EXPRESSION OF GENES IMPORTANT FOR THE DEVELOPMENT OF CNS MIDLINE CELLS
    NAMBU, JR
    FRANKS, RG
    HU, S
    CREWS, ST
    [J]. CELL, 1990, 63 (01) : 63 - 75
  • [9] Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A
    Oegema, R.
    de Klein, A.
    Verkerk, A. J.
    Schot, R.
    Dumee, B.
    Douben, H.
    Eussen, B.
    Dubbel, L.
    Poddighe, P. J.
    van der Laar, I.
    Dobyns, W. B.
    van der Spek, P. J.
    Lequin, M. H.
    de Coo, I. F. M.
    de Wit, M. C. Y.
    Wessels, M. W.
    Mancini, G. M. S.
    [J]. MOLECULAR SYNDROMOLOGY, 2010, 1 (03) : 113 - 120
  • [10] Spatial and temporal localization during embryonic and fetal human development of the transcription factor SIM2 in brain regions altered in Down syndrome
    Rachidi, M
    Lopes, C
    Charron, G
    Delezoide, AL
    Paly, E
    Bloch, B
    Delabar, JM
    [J]. INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, 2005, 23 (05) : 475 - 484