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| Laterality disorders and isomerism v4.5 | MNS1 |
Ida Ertmanska changed review comment from: 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. 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).; to: 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). |
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| Laterality disorders and isomerism v4.5 | MNS1 |
Ida Ertmanska changed review comment from: 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. This gene is associated with AR Ciliary dyskinesia, primary, 3, with or without situs inversus, 608644 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).; to: 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. 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). |
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| Laterality disorders and isomerism v1.5 | MNS1 |
Zornitza Stark gene: MNS1 was added gene: MNS1 was added to Laterality disorders and isomerism. Sources: Literature Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MNS1 were set to 31534215; 30148830 Phenotypes for gene: MNS1 were set to Heterotaxy; male infertility Review for gene: MNS1 was set to GREEN gene: MNS1 was marked as current diagnostic Added comment: 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 |
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| Laterality disorders and isomerism v0.89 | DNAH5 | Louise Daugherty Phenotypes for gene: DNAH5 were changed from to Ciliary dyskinesia, primary, 3, with or without situs inversus, 608644 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v0.88 | DNAH5 | Louise Daugherty Publications for gene: DNAH5 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v0.87 | DNAH5 | Louise Daugherty Mode of inheritance for gene: DNAH5 was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v0.51 | DNAH5 | Matthew Edwards reviewed gene: DNAH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261302, 11788826, 11062149; Phenotypes: OMIM 608644 Ciliary dyskinesia, primary, 3, with or without situs inversus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v0.3 | DNAH5 |
Louise Daugherty Source Expert Review Green was added to DNAH5. Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| Laterality disorders and isomerism v0.2 | DNAH5 | Louise Daugherty reviewed gene: DNAH5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v0.1 | DNAH5 |
Louise Daugherty gene: DNAH5 was added gene: DNAH5 was added to Laterality disorders and isomerism. Sources: NHS GMS Mode of inheritance for gene: DNAH5 was set to |
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