ClinGen Dosage Sensitivity Curation Page

7q11.23 recurrent distal region (includes HIP1, YWHAG)

  • Curation Status: Complete
  • id: ISCA-46291
  • Date last evaluated: 2018-12-31
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 2
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000007.13) ()
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21109226 Ramocki et al. (2010) describe six patients (patients 1, 3, 6-8, 10) with deletions of the 7q11.23 recurrent distal region. Clinical findings in common across patients included: seizures (all patients), global developmental delay and intellectual disability, hyperactivity, and autism spectrum disorder. This deletion was not identified in over 20,000 individuals in a control cohort. Inheritance was known in five cases: three were paternally inherited and two were maternally inherited. All carrier parents were reported to have either a history of epilepsy and/or mild intellectual disability/learning difficulties. Three additional patients had smaller deletions that included HIP1, but not YWHAG, suggesting that HIP1 is the candidate gene for the neurological phenotypes seen in these patients.
16971481 Edelmann et al. (2007) describe one patient with a deletion of the 7q11.23 recurrent distal region. The clinical features described in this patient included cognitive behavioral issues, asymmetric abnormally shaped ears, wide spaced teeth, wide mouth, and prominent lips. The deletion was identified by BAC array, the breakpoints were mapped using quantitative PCR, and microsatellite analysis confirmed that the deletion was de novo, arising on the paternally inherited chromosome.

Haploinsufficiency phenotype comments:

Evidence in support of the pathogenicity of 7q11.23 recurrent distal region* (LCR-C to LCR-D; includes HIP1, YWHAG) deletion is emerging at this time. Deletion of the 7q11.23 recurrent distal region has been reported in seven individuals with neurodevelopmental phenotypes, including seizures. There is supportive evidence that larger deletions that include this region and the adjacent Williams Beuren syndrome (WBS) region result in a more severe WBS phenotype, including infantile spasms and epilepsy (see Fusco et al., 2014; PMID 23756441). Most of the reported deletions have been inherited from a parent (who is also affected). Although this deletion was only observed in the patient population in a large case-control study (Coe et al., 2014, reviewed below), due to its relative rarity, statistical significance for enrichment of distal 7q11.23 deletions amongst patients has not been observed (reviewed below). Therefore the haploinsufficency score is 2. *The 7q distal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions involving recurrent breakpoints (BP) within the 7q11.23 (LCR-C to LCR-D; includes HIP1, YWHAG) region. This region is located distal to the recurrent Williams Beuren syndrome (WBS) region. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Additional literature is summarized below: 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 7q11.23 recurrent distal region were observed in 5/29,085 cases versus 0/19,584 controls (p= 0.0762, LR=INF (0.0775 to INF)).

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
21109226 Ramocki et al. (2010) describe one patient (patient 12) with a duplication of the 7q11.23 recurrent distal region. The clinical features described in this patient included biopolar disorder, ADHD, and aggression. This patient had a sister who was a carrier of this duplication with clinical features including speech delay, ADHD and aggression; however, an additional CNV was identified (11p14.3p14.2 deletion, breakpoints not indicated). Inheritance was unknown, but was not identified in the mother. One additional patient had smaller duplication (paternally inherited) that included HIP1, but not YWHAG.
27867344 Faundes et al. (2016) describe one patient (patient 5) with a duplication of the 7q11.23 recurrent distal region. The clinical features described in this patient were similar to Prader-Willi syndrome, and included dysmorphic features (broad face, straight eyebrows, deep-set eyes, protruding nasal tip, and high-arched palate), obesity, hyperphagia, insulin resistance, mild intellectual delay, behavioral differences including aggressiveness and ADHD, anxiety, and impulsive control issues. The patient had negative methylation-sensitive PCR testing for the Prader-Willi imprinting center and a normal karyotype. The duplication was identified by chromosomal microarray, and confirmed using MLPA. Testing of parents by microarray confirmed that this duplication was de novo.

Triplosensitivity phenotype comment:

Evidence supporting pathogenicity of 7q11.23 recurrent distal region* (LCR-C to LCR-D; includes HIP1, YWHAG) duplication is currently limited at this time. Due to the limited number of reported cases involving this region, phenotypic variability amongst duplication carriers, and insufficient significance estimates (limited number of observations) from case-control studies (summarized below), the current triplosensitivity score is 1. *The 7q distal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to duplications involving recurrent breakpoints (BP) within the 7q11.23 (LCR-C to LCR-D; includes HIP1, YWHAG) region. This region is located distal to the recurrent Williams Beuren syndrome (WBS) region. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Additional literature is summarized below: 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 7q11.23 recurrent distal region were observed in 1/29,085 cases versus 0/19,584 controls (p= 0.598, LR=INF (0.0364 - INF)).