ClinGen Dosage Sensitivity Curation Page

17q12 recurrent (RCAD syndrome) region (includes HNF1B)

  • Curation Status: Complete
  • id: ISCA-37432
  • Date last evaluated: 2015-08-10
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: (NC_000017.10) ()

Haploinsufficiency phenotype comments:

Deletion of 17q12 encompassing the gene HNF1B (formerly TCF2) is associated with RCAD (renal cysts and diabetes) syndrome, also known as MODY5 (maturity-onset diabetes of the young type 5). Phenotypes associated with 17q12 deletion include genitourinary abnormalities (particularly renal cysts, glomerulocystic kidney disease, and renal dysplasia), diabetes (typically diagnosed in the second decade of life), autism spectrum disorders (ASD), neurocognitive impairment, and schizophrenia (see PMIDs 16249435, 17924346, 19844256, 21055719). Both variable expressivity and incomplete penetrance for 17q12 deletions have been demonstrated. Rosenfeld et al., 2013 (PMID 23258348) reported 17q12 deletions are enriched relative to controls (29/33,226 cases vs. 2/22,246 controls; p<0.0001) with a penetrance estimate of 34.4% (13.7-70.0; 95% CI). This report expanded the number of both clinical and control cases from an earlier study (Cooper et al., 2011; PMID 21841781). Kaminsky et al., 2011 (PMID 23258348) also reported significant enrichment of this deletion in the clinical population (p=0.00015). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region.

Triplosensitivity phenotype comment:

Duplication of 17q12 encompassing the gene HNF1B (formerly TCF2) is associated with a variable clinical presentation that may include developmental delay/intellectual disability, behavioral problems, epilepsy, microcephaly, and brain abnormalities. Mild facial dysmorphism, renal abnormalities, esophageal atresia, abnormal genitalia, heart and ocular abnormalities have also been reported (see PMIDs 19844256, 23307502, and others). Variable expressivity and incomplete penetrance for 17q12 duplications have been demonstrated. Rosenfeld et al., 2013 (PMID 23258348) reported 17q12 duplications are enriched relative to controls (37/33,226 cases vs 5/22,246 controls; p<0.0001) with a penetrance estimate of 21.1% (10.6-39.5%, 95% CI). This report expanded the number of both clinical and control cases from an earlier study (Cooper et al. 2011; PMID 21841781). Kaminsky et al., 2011 (PMID 23258348) also reported significant enrichment of this duplication in the clinical population (p=0.022). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region.