ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

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.

Evidence for Triplosenstive Phenotype

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.