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Eur J Hum Genet. 2019 Sep 18. doi: 10.1038/s41431-019-0489-z. [Epub ahead of print]

MNS1 variant associated with situs inversus and male infertility.

Author information

1
Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
2
Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Gladstone Road, Exeter, EX1 2ED, UK.
3
Department of Ophthalmology, University of Arizona College of Medicine, Tucson, AZ, USA.
4
Department of Cardiology, Royal Devon and Exeter NHS Foundation Trust (Wonford), Barrack Road, Exeter, EX2 5DW, UK.
5
Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. A.H.Crosby@exeter.ac.uk.
6
Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. E.Baple@exeter.ac.uk.
7
Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Gladstone Road, Exeter, EX1 2ED, UK. E.Baple@exeter.ac.uk.

Abstract

Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left-right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.

PMID:
31534215
DOI:
10.1038/s41431-019-0489-z

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