Laterality disorders and isomerism

Gene: MNS1

Green List (high evidence)

Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene will be recommended for promotion to Green if agreed under additional Expert Review.

Created: 29 Oct 2025, 1:33 p.m. | Last Modified: 2 Jan 2026, 3:41 p.m.

Panel Version: 4.9

PMID: 38920647 Hjejj et al., 2024
Report of four affected individuals and a fetus with motile ciliopathy and biallelic variants in MNS1 (four families from Afghanistan, Egypt, and Kosovo). 2 families were confirmed to be consanguineous. 4/4 affected individuals presented with laterality defects, including one male individual with heterotaxia and complex congenital heart defects. One patient displayed a pronounced respiratory phenotype. Heterozygous family members were unaffected.
Identified variants:
c.724C>T, p.(Arg242*) - Highest MAF = 0.001176 (South Asian population, includes 1 homozygote, gnomAD v4) - likely too high to cause recessive disease.
c.1084G>T, p.(Glu362*) - Highest MAF = 0.00003295 (South Asian population, no homozygotes, gnomAD v4).
c.678_680del, p.(Glu226del) - Highest MAF = 0.00005104 (Admixed American, no homozygotes, gnomAD v4).
Sequencing method: trio exome for 1 family; panel including 'all published PCD and motile ciliopathy-related genes' applied for 3 families.

PMID: 31534215 Leslie et al., 2019
Situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family - identified a biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)] - rare, MAF in gnomAD v4 = 0.000002545.
WT and heterozygous family members were unaffected, while in homozygous individuals disease presented with incomplete penetrance (4/6 exhibited situs inversus and 2/6 - situs solitus, normal organ position).
Seq method: genome-wide SNP mapping and WES.

PMID: 30148830 Ta-Shma et al., 2018
Identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families:
1) homozygous nonsense mutation c.724T>C, p.(Arg242*) in four males with laterality defects and infertility - Turkish and Israeli origins; MAF as above, relatively common in general population
2) a homozygous nonsense mutation c.607C>T, p.(Gln203*) in MNS1 in one Israeli female with laterality defects and recurrent respiratory infections. Variant c.607C>T is rare (MAF = 0.000005937, gnomAD v4, no homoz). Patient additionally carried a homozygous mutation in DNAH5 - a known PCD gene; family members homozygous for the DNAH5 mutations but not the MNS1 variant also had PCD. The contribution of each gene cannot be decoupled.
Sequencing method: linkage analysis & WES.

Functional evidence:
PMID: 22396656 Zhou et al., 2012
Mns1-deficient mice; phenotype: situs inversus in 8/36, left isomerism (heterotaxy) in 6/36 and situs solitus in 22/36 - supports incomplete penetrance of the laterality defect phenotype in humans.

This gene is associated with AR Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).

Created: 29 Oct 2025, 1:23 p.m. | Last Modified: 29 Oct 2025, 1:44 p.m.

Panel Version: 4.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM: 618948; situs inversus, MONDO:0010029

Publications

• 22396656
• 30148830
• 31534215
• 38920647

Green List (high evidence)

Additional publication reports 4 families (5 individuals) with laterality defects (PMID:38920647)

Created: 30 Jul 2025, 12:18 p.m. | Last Modified: 30 Jul 2025, 12:18 p.m.

Panel Version: 4.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Laterality defects; ciliopathy disorder

Publications

• PMID: 38920647

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Submitted on behalf of NHS GMS "Limited evidence, two studies, would prefer more evidence for upgrading to green."

Created: 8 Mar 2022, 11:09 a.m. | Last Modified: 8 Mar 2022, 11:09 a.m.

Panel Version: 1.47

After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 8 Mar 2022, 11:09 a.m. | Last Modified: 8 Mar 2022, 11:11 a.m.

Panel Version: 1.47

Comment on list classification: This gene has been added as an Amber gene and will be promoted to a Green gene at the next major update. It has been tagged with "for-review".

Created: 26 Aug 2020, 12:42 p.m. | Last Modified: 26 Aug 2020, 12:42 p.m.

Panel Version: 1.11

New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM. There are 2 mouse models (PMID: 22396656, 30148830) that resembled the human disease. Therefore, there is enough evidence for this gene to be rated Green.

Created: 26 Aug 2020, 12:41 p.m. | Last Modified: 26 Aug 2020, 12:41 p.m.

Panel Version: 1.10

Green List (high evidence)

Eight families reported altogether. However, four are Amish and share same homozygous founder variant, and some of the other reported families are consanguineous and share another founder variant. A reported female with a third variant, also had a homozygous variant in DNAH5 with a blended phenotype postulated.
Sources: Literature

Created: 2 May 2020, 2:37 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Heterotaxy; male infertility

Publications

• 31534215
• 30148830

Variants in this GENE are reported as part of current diagnostic practice