Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects

Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal oppo...

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Published in:	Frontiers in medicine Vol. 8; p. 724826
Main Authors:	Alsafwani, Rabab Said, Nasser, Khalidah K., Shinawi, Thoraia, Banaganapalli, Babajan, ElSokary, Hanan Abdelhalim, Zaher, Zhaher F., Shaik, Noor Ahmad, Abdelmohsen, Gaser, Al-Aama, Jumana Yousuf, Shapiro, Adam J., O. Al-Radi, Osman, Elango, Ramu, Alahmadi, Turki
Format:	Journal Article
Language:	English
Published:	Frontiers Media S.A 13-09-2021
Subjects:	gene expression laterality defects Medicine microfilament variant whole exome sequencing
Online Access:	Get full text
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Summary:	Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal opportunity to discover the novel molecular basis of diseases owing to the high rate of consanguinity and genetic disorders. Therefore, in the present study, we studied the molecular basis of LD in Arab patients, using next-generation sequencing method. We discovered an extremely rare novel missense variant in MYO1D gene (Pro765Ser) presenting with visceral heterotaxy and left isomerism with polysplenia syndrome. The proband in this index family has inherited this homozygous variant from her heterozygous parents following the autosomal recessive pattern. This is the first report to show MYO1D genetic variant causing left–right axis defects in humans, besides previous known evidence from zebrafish, frog and Drosophila models. Moreover, our multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) analysis has suggested that Ser765 causes minor structural drifts and stability changes, potentially affecting the biophysical and functional properties of MYO1D protein like calmodulin binding and microfilament motor activities. Functional bioinformatics analysis has shown that MYO1D is ubiquitously expressed across several human tissues and is reported to induce severe phenotypes in knockout mouse models. In conclusion, our findings show the expanded genetic spectrum of LD, which could potentially pave way for the novel drug target identification and development of personalised medicine for high-risk families.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Ibrahim Jelaidan, King Faisal Cardiac Center, King Abdulaziz Medical City, Saudi Arabia; Prashantha Karunakar, PES University, India Edited by: Thirumal Kumar D., Meenakshi Academy of Higher Education and Research, India These authors have contributed equally to this work This article was submitted to Precision Medicine, a section of the journal Frontiers in Medicine
ISSN:	2296-858X 2296-858X
DOI:	10.3389/fmed.2021.724826