ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37501
  • Date last evaluated: 2018-11-19
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2


Location Information

  • 17q23.1-q23.2
  • GRCh37/hg19 chr17: 58,113,002-60,275,809
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr17: 60,035,641-62,198,448
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000017.10) ()
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Deletion involving the 17q23.1q23.2 recurrent region (including genes TBX2 and TBX4) has been reported in multiple individuals with overlapping, but variable clinical features including hand and foot anomalies, heart defects, microcephaly, postnatal growth retardation, musculoskeletal abnormalities, and hearing loss. Dysmorphic facial features have been observed in most individuals, but without a specific, characteristic constellation of features across patients. In cases where parental testing was performed, all have been de novo. Although case-control data supporting enrichment of 17q23.1q23.2 deletion in the clinical population are currently lacking (see below), due to phenotypic consistency across carriers and de novo inheritance, the haploinsufficiency score is 3. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: PMID 21271665: Nimmakayalu et al. (2011) reported an individual with a 3.75 Mb deletion (chr17:53,784,074-57,536,545 from NCBI 36/hg18) involving the 17q22q23.1 region identified by microarray. This deletion overlaps with the recurring 2.2 Mb deletion described in the case series from Ballif et al. (PMID: 20206336) but does not lie within paired segmental duplications. Clinical features of this individual were very similar to those reported by Ballif but this subject did not have any major limb anomalies. Additionally, echocardiogram at age 5 months did not show any structural cardiac defects. Case-control studies: PMID 25217958: Coe et al (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of the recurrent 17q23.1q23.2 region were observed in 1/29,085 cases versus 0/19,584 controls (p=0.5980; LR: Inf, CI: 0.0364 to inf).

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
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.

Triplosensitivity phenotype comment:

Duplication of the recurrent 17q23.1q23.2 region (including genes TBX2 and TBX4) has been reported in four non-syndromic clubfoot cases. In these families, the duplications were found to segregate in individuals with a range of phenotypes, including severe clubfoot residuals, hip dysplasia, short wide feet with short abnormal toes; however, four individuals carrying the duplications were phenotypically normal. These studies show incomplete penetrance and variable expressivity for duplications in this region. Furthermore, there appeared to be a male preponderance for the clubfoot phenotype among duplication carriers. Case-control data supporting enrichment of 17q23.1q23.2 duplication in the clinical population are currently lacking (see below). Due to a relatively limited number of cases of 17q23.1q23.2 duplications in the literature, reported incomplete penetrance/variable expressivity, and lack of statistical enrichment, the triplosensitivity score is rated 2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: PMID 22678995: Lu et al. (2012) evaluated 605 probands (from 148 multiplex and 457 simplex families) with nonsyndromic clubfoot for copy number changes. One multiplex family (0.68%) had a 350 kb microduplication at 17q23.2 which included the complete duplication of TBX4 and NACA2 and partial duplication of BRIP1 [0.35 Mb duplication at chromosome 17: 59502551-59821945 (HG build 19)]. This duplication was identified in a single large non-Hispanic white family with 16 cases of clubfoot (11 genotyped) and 9 cases (7 genotyped) of other foot anomalies segregating in an autosomal dominant pattern through six generations. The phenotypes observed in the family range from severe clubfoot residuals to short wide feet with short abnormal toes. Family members not carrying this duplication (designated as WT) did not manifest clubfoot or other related features. Case-control studies: PMID 25217958: Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplications of the recurrent 17q23.1q23.2 region were observed in 0/29,085 cases and 0/19,584 controls.