ClinGen Dosage Sensitivity Curation Page

17q23.1q23.2 recurrent region (includes TBX2, TBX4)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
20206336 Ballif et al. (2010) reported seven individuals with deletions involving the 17q23.1q23.2 region identified by aCGH, including a recurrent 2.2 Mb deletion observed in six individuals (patients 1, 3, 4, 5, 6, 7) and a 2.8 Mb deletion observed in one individual (patient 2). The 2.2 Mb deletions were all mediated by NAHR between flanking segmental duplications, while the proximal breakpoint of the 2.8 Mb deletion fell between segmental duplications. Clinical features were variable and included hand and foot anomalies including long, thin fingers and toes (7 of 7); heart defect(s), in most cases either patent ductus arteriosus or atrial septal defect (ASD) (6 of 7); low birth weight (5 of 7); microcephaly or relative microcephaly (5 of 7); postnatal growth retardation (5 of 7); musculoskeletal abnormalities of varying severity (4 of 7); pulmonary hypertension (3 of 7); hearing loss (2 of 7); and aggressive behavior (2 of 7). Parental follow up studies were performed for five of the seven cases (patients 2 and 4?7), and all deletions were de novo.
22052739 Schonewolf-Greulich et al. (2011) reported two individuals with deletions involving the 17q23.1q23.2 region. Both subjects had clinical features consistent with the reported phenotype, including developmental delay and hearing loss. Both deletions were de novo.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
20598276 Alvarado et al. (2010) performed genome-wide copy number analysis on 66 isolated idiopathic clubfoot probands with at least one affected first-degree relative. Three of 66 probands with familial isolated clubfoot carry a chromosome 17q23.1q23.2 duplication [2.2 Mb duplication at chromosome 17: 55457520?57693617 (hg18 build of the UCSC genome browser)]. This duplication segregated with idiopathic clubfoot in all three families, but with incomplete penetrance. Clubfoot was present in seven patients with the microduplication and absent in three patients (approximate penetrance of 70%). All cases with clubfoot were male, and clubfoot was bilateral in all except one case. This 17q23.1q23.2 duplication was not present in 700 controls evaluated with the same platform and is not reported in the Database of Genomic Variants.
24592505 Peterson et al. (2014) reported a male proband with multiple congenital anomalies including bilateral congenital clubfoot carrying a 2.15 Mb duplication of the 17q23.1 region [17: 55471610-57621696 (hg18)]. A male sibling with unilateral clubfoot and a phenotypically normal female sibling were both confirmed carriers of the duplication inherited from a phenotypically normal mother.

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.