ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000004.11) (NC_000004.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11369996 Jumlongras et al. (2001) Sanger sequenced MSX1 coding regions and their flanking intronic regions and found a S202X nonsense variant co-segregating with the nail dysplasia and congenitally missing teeth in 9 affected members in a three-generation family. This variant was not present in 132 normal unrelated controls and is also not present in gnomAD v2.1.1.
10742093 Van den Boogaard et al. (2000) studied a Dutch family with tooth agenesis and various combinations of cleft palate only and cleft lip and cleft palate. Sanger sequencing results showed a nonsense variant (Ser104stop) in exon 1 of MSX1 in all 12 affected family members with tooth agenesis and/or cleft lip/palate, but not in the three unaffected. Ser14stop was also not present in 102 normal controls, and is also not present in gnomAD v2.1.1.
15264286 De Muynck et al. (2004) analyzed the MSX1 gene in 55 individuals from 40 families with hypodontia with or without cleft lip and/or palate and identified heterozygosity for a truncating mutation (Q187X) in 3 affected members of 1 family with severe hypodontia.

Haploinsufficiency phenotype comments:

Loss of function variants in MSX1 have been reported in individuals with tooth agenesis, either in isolation or accompanied by other anomalies, such as nail dysplasia, and/or orofacial clefts. Additional evidence includes: PMID: 30134957 Xin et al. (2018) used Sanger sequencing to identify the cause of familial nonsyndromic oligodontia in a Chinese family, and found a novel frameshift variant (c.128_147del20, p.Met43Serfsx125), in exon1 of MSX1. This variant cosegregated with the tooth agenesis phenotype in this family. Human dental pulp stem cells (hDPSCs) transfected with mutant MSX1 plasmid showed decreased capacity of osteo odontogenic differentiation compared with those transfected with control MSX1 plasmid. PMID: 26030286 Tatematsu et al. (2015) reported a Japanese family with nonsyndromic tooth agenesis. cDNA analysis confirmed that a 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). PMID: 16498076 Kim et al. (2006) identified an MSX1 frameshift mutation (g.62dupG, p.G22RfsX168) that causes non-syndromic autosomal-dominant oligodontia, featuring the absence of multiple permanent teeth, including all second bicuspids and mandibular central incisors. The dominant phenotype is apparently due to haploinsufficiency. PMID: 33419968 Zheng et al. (2021) performed WES and Sanger sequencing to identify the causal gene variants in five families with nonsyndromic oligodontia. Five novel MSX1 heterozygous variants were identified: three missense variants [c.662A>C (p.Q221P), c.670C>T (p.R224C), and c.809C>T (p.S270L)], one nonsense variant [c.364G>T (p.G122*)], and one frameshift variant [c.277delG (p.A93Rfs*67)]. Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P, p.R224C, p.G122*, and p.A93Rfs*67 variants compared to the wild type. Three variants (p.Q221P, p.G122*, and p.A93Rfs*67) were classified as pathogenic or likely pathogenic. Of note, some of the deletions in Wolf-Hirschhorn Syndrome (WHS) patients (caused by microdeletion of 4p16.3) are bigger and encompass MSX1. PubMed: 12563561. Zollino et al (2003) studied a total of 8 WHS patients carrying a 4p16.3 microdeletion. The extent of each deletion was established by FISH, with a cosmid contig spanning the entire genomic region from MSX1 in the distal half of 4p16.1 to the subtelomeric locus D4S3359. Individuals with WHS are more prone to anomalies in dental structure. Cone-shaped and taurodontic teeth were observed. Multiple tooth agenesis with over-retained deciduous dentition might be associated with MSX1-gene impairment. PubMed: 14630905. Nieminen et al. (2003) examined 8 Finnish patients with abnormalities of 4p, including 7 with Wolf-Hirschhorn syndrome (WHS). Five of the WHS patients presented with agenesis of several teeth. FISH showed these five patients are lacked one copy of MSX1, while the other three had two copies.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity