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

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...

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Published in:European journal of medical genetics 2020-01, Vol.63 (1), p.103635-103635, Article 103635
Main Authors: Muthusamy, Babylakshmi, Nguyen, Thong T., Bandari, Aravind K., Basheer, Salah, Selvan, Lakshmi Dhevi N., Chandel, Deepshikha, Manoj, Jesna, Gayen, Srimonta, Seshagiri, Somasekar, Chandra Girimaji, Satish, Pandey, Akhilesh
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
Adolescent
Autism Spectrum Disorder - genetics
Autism Spectrum Disorder - pathology
Calvarial sutures
Child
Child, Preschool
Comparative Genomic Hybridization
Cranial sutures
Cranial Sutures - diagnostic imaging
Cranial Sutures - pathology
Craniofacial Abnormalities - genetics
Craniofacial Abnormalities - pathology
Craniosynostosis
Developmental delay
Exome - genetics
Female
Growth Disorders - genetics
Growth Disorders - pathology
Humans
Intellectual Disability - genetics
Intellectual Disability - pathology
Male
Metopic suture
Protein Isoforms - genetics
RNA Splice Sites - genetics
Tumor Suppressor Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Whole Exome Sequencing
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Summary: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.
ISSN:1769-7212
1878-0849
DOI:10.1016/j.ejmg.2019.02.007