ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-23568
• Date last evaluated: 2020-09-23
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/3239
• OMIM: https://omim.org/entry/610713

Location Information

• 2q31.1
• GRCh37/hg19 chr2: 176,957,532-176,960,666

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: SYNPOLYDACTYLY 1; SPD1

Evidence for loss of function phenotype

PubMed ID	Description
31611522	In 2019, Guo et al. used trio whole-exome sequencing (trio-WES) on an individual with synopolydactyly (SPD) and their parents. Analysis identified a nonsense variant (p.Gln287Ter) in HOXD13 in the proband and the affected father. Per the authors, ?Mutation Taster, Human Splicing Finder and EX-SKIP predicted that the heterozygous mutation (c.859 C>T) would result in haploinsufficiency of HOXD13 protein through nonsense-mediated mRNA decay (NMD) and splicing abnormality, which might disrupt the integrity and reduce the expression level of the HOXD13 protein (loss-of-function).? This variant was absent in the unaffected mother and grandmother.
22233338	In 2012, Jamsheer et al. used PCR, direct sequencing, and multiplex ligation-dependent analysis (MLPA) on a family with brachydactyly (BDE) to identify potential variants in HOXD13. The authors identified a nonsense variant in the proband and her affected father (p.R274X).
9758628	In 1998, Goodman et al. used PCR to identify potential variants in HOXD13 in 2 families with digital abnormalities. In family 1, a 14-base pair deletion resulting in a frameshift variant and truncated protein product was identified in the proband and 3 other family members. However, only the proband displayed digital abnormalities. In family 2, a different frameshift variant resulting in a premature stop codon was identified in the proband, 4 affected family members, and 2 unaffected family members.

• Loss of function phenotype comments: There are many variations in disease phenotype with HOXD13 including Brachydactyly, Syndactyly, Synpolydactyly with foot anomalies, and VACTERL association. Additional cases: PMID: 21814222 In 2011, Kurban et al. used PCR and direct sequencing on consanguineous family members with variable presentations of synopolydactyly (SPD). Analysis identified the nonsense variant p.Q248X in HOXD13. 6 individuals carry the variant in a heterozygous manner and are unaffected, 16 individuals are affected. Of these affected individuals, 10 are homozygous for the variant and 6 are heterozygous for the variant. The authors note that individuals carrying the variant in the homozygous state were more severely affected than those with the heterozygous presentation who either displayed mild SPD or were unaffected. Per the authors, ?because of the high rate of consanguinity, the inheritance pattern was most likely autosomal recessive, while there was also the possibility of autosomal dominant inheritance with incomplete penetrance. We initially performed parametric linkage analysis, which was non-revealing. We then performed nonparametric linkage analysis and identified linkage to a region on chromosome 2 containing the HOXD13 gene, under an autosomal dominant inheritance model.? PMID: 27254532 In 2017, Wang et al. used whole exome sequencing (WES) on a family with synopolydactyly (SPD). Analysis identified a novel nonsense variant (p.R186X) resulting in protein truncation in HOXD13 in the proband. The variant was identified in 4 affected relatives and absent in 3 unaffected relatives who were given testing. PMID: 12900906 In 2003, Kan et al. used PCR on a family with limb malformations. Analysis identified a variant affecting splicing in HOXD13 in the proband and 2 other affected family members (758-2delA). PMID: 24055421 In 2013, Shi et al. used PCR and direct sequencing on a family with type II synopolydactyly (SPD1). The authors identified a splice site variant in the proband and their 4 affected family members. PMID: 17236141 In 2007, Zhao et al. used two-point linkage analysis and mutation identification on a family with limb abnormalities. The authors identified a 21-bp deletion in HOXD13 in 15 individuals of the family. PMID: 19006232 In 2008, Garcia-Barcelo et al. used PCR on one patient with VACTERL and identified a de novo 21-bp deletion in HOXD13. PMID: 32789964 In 2020, Zhang et al. used PCR on a family with brachydactyly type A (BDA). A frameshift deletion in HOXD13 was shown in 4 of the affected individuals of the family. PMID: 28794915 In 2017, Radhakrishnan et al. used Sanger sequencing on a mother and fetus with synpolydactlyly and identified a deletion in HOXD13 in both individuals.

Evidence for Triplosenstive Phenotype

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

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.