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Eur J Med Genet. 2019 Feb 21. pii: S1769-7212(18)30478-6. doi: 10.1016/j.ejmg.2019.02.007. [Epub ahead of print]

Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome.

Author information

1
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India; Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India; Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
2
Department of Molecular Biology and Metabolic Disease, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
3
Department of Child and Adolescent Psychiatry, NIMHANS, Hosur Road, Bangalore, 560029, India.
4
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
5
Department of Molecular Reproduction, Development and Genetics, Division of Biological Sciences, Indian Institute of Science, Bangalore, India.
6
Department of Child and Adolescent Psychiatry, NIMHANS, Hosur Road, Bangalore, 560029, India. Electronic address: girimaji@nimhans.kar.nic.in.
7
Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India; Department of Laboratory Medicine and Pathology, Rochester, MN, 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address: pandey.akhilesh@mayo.edu.

Abstract

Say-Meyer syndrome is a rare and clinically heterogeneous syndrome characterized by trigonocephaly, short stature, developmental delay and hypotelorism. Nine patients with this syndrome have been reported thus far although no causative gene has yet been identified. Here, we report two siblings with clinical phenotypes of Say-Meyer syndrome with moderate to severe intellectual disability and autism spectrum disorder. Cytogenetics and array-based comparative genomic hybridization did not reveal any chromosome abnormalities or copy number alterations. Exome sequencing of the patients revealed a novel X-linked recessive splice acceptor site variant c.145-2A > G in intron 5 of HUWE1 gene in both affected siblings. RT-PCR and sequencing revealed the use of an alternate cryptic splice acceptor site downstream, which led to deletion of six nucleotides resulting loss of two amino acids p.(Cys49-Glu50del) in HUWE1 protein. Deletion of these two amino acids, which are located in a highly conserved region, is predicted to be deleterious and quite likely to affect the function of HUWE1 protein. This is the first report of a potential candidate gene mutation for Say-Meyer syndrome, which was initially described four decades ago.

KEYWORDS:

Calvarial sutures; Cranial sutures; Craniosynostosis; Developmental delay; Metopic suture

PMID:
30797980
DOI:
10.1016/j.ejmg.2019.02.007
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