Submission Details

The ZSWIM6 gene is located at chromosome 5q12.1, has 14 exons, and encodes a 133.kDa protein that belongs to a group of proteins described by the SWIM-type zinc finger domain. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: acromelic frontonasal dysostosis (OMIM:603671) and neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (OMIM:617865). Here, we curate autosomal dominant acromelic frontonasal dysostosis (MONDO:0011359).

ZSWIM6 was first reported in relation to autosomal dominant acromelic frontonasal dysostosis in 2014 (Smith et al., 2014, PMID: 25105228). Patients with this disease have been identified as heterozygous for a de novo missense mutation (c.3487C>T, p.Arg1163Trp) in the ZSWIM6 gene. Smith et al 2014 postulate a gain-of-function effect of the mutation because of the differing phenotype in individuals with heterozygous deletions of the gene versus those diagnosed with acromelic frontonasal dysostosis. Common phenotypes for individuals with this variant include large fontanelle, hypertelorism, bifid nasal tip, nasal clefting, brachycephaly, median cleft face, carp-shaped mouth, interhemispheric lipoma, tibial hypoplasia/aplasia, symmetric preaxial polydactyly of the feet, bilateral clubbed foot, thickened nails of halluces, and intellectual disability. Due to the multitude of cases with this rare and distinct phenotype and the de novo occurrence in a highly constrained gene, the expert panel decided to award an additional 0.4 points per proband who has radiographic imaging and/or publicly available images.

One missense variant in three publications (PMID: 25105228, 26706854, 33776626) and four clinical testing laboratories (SCV000568856.6, SCV004011595.1, SCV000742103.4, SCV000986913.2) have been included in this curation. De novo status has been confirmed for 12 out of the 14 probands reported here. This gene disease relationship is also supported by expression studies and a knockout mouse model (PMIDs: 25105228, 28433741).

In summary, there is definitive evidence supporting the relationship between ZSWIM6 and autosomal dominant acromelic frontonasal dysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 08/24/2023 (SOP Version 9).