ClinGen Dosage Sensitivity Curation Page

15q24 recurrent region (C-D) (includes SIN3A)

  • Curation Status: Complete
  • id: ISCA-46300
  • Date last evaluated: 2020-01-13
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 0


Location Information

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Evidence for haploinsufficiency phenotype
PubMed ID Description
27399968 Witteveen et al. (2016), reported 3 patients with 15q24 LCRC-D deletions. These patients presented with developmental delay, intellectual disability, structural brain anomalies, microcephaly, dysmorphic craniofacial features, thin hair, hypermobile joints, and additional clinical findings. The dysmorphic craniofacial features were variable, with the recurrent features including downslanting palpebral fissures, deep set eyes, small mouth, and a pointed chin. Parental testing showed that each of these deletions was de novo. A fourth individual with a deletion in this region was reported by this group (Patient 4); however, the distal breakpoint for that patient's deletion was proximal to 15q24 LCRD. The clinical findings in Patient 4 were similar to those with breakpoints in LCRD including developmental delay, downslanting palpebral fissures, small mouth, and a pointed chin. The deletion in patient 4 was also found to be de novo. The authors of this paper also report nine patients (from five families) with loss-of-function type variants in SIN3A, which lies within the 15q24 LCRC-D region. These patients presented with similar clinical findings to the patients with 15q24 LCRC-D deletions.
22180641 Mefford et al. (2012) reported one patient (Patient 14) with a 15q24 LCRC-D deletion. This patient presented with borderline mild intellectual disability, short stature, structural brain abnormalities, possible Asperger, telecanthus, bilateral epicanthi, hypermobile joints, and bilateral short 5th fingers. The deletion in this patient was found to represent a de novo event. The authors also reported a second individual (Patient 13) with a smaller de novo deletion within the 15q24 LCRC-D region; however, the distal breakpoint for that patient?s deletion was proximal to 15q24 LCRD. That patient was reported to have mild intellectual disability, developmental delay (speech and motor), obsessive compulsive behaviors, microcephaly, a round face, short 5th metacarpals, toe syndactyly, and additional clinical findings.

Haploinsufficiency phenotype comments:

Deletion of the 15q24 recurrent region (C-D)* has been reported in at least 4 patients in association with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions in this region (PMID: 27399968 and 27399968). These patients were found to have a similar clinical presentation to patients with the typical 15q24 LCRC-D deletion. Parental studies have been performed on each of the deletions in this region (6 total), and in each case it was found to be de novo. *The 15q24 region contains a cluster of low-copy repeats (LCRs), referred to as 15q24 LCRA through 15q24 LCRE (15q24 LCRA-E), that mediate recurrent copy number changes through non-allelic homologous recombination. See El-Hattab et al. (2010), Figure 1 for a description of this region (PMID: 22180641). Note that a variety of 15q24 LCR-mediated rearrangements are possible, and CNVs overlapping this region should be evaluated based on reports of patients with similar genomic content. Note that genes used as landmarks are not necessarily the only genes causative of the phenotype(s) associated with the region. Additional relevant literature is cited and summarized below: Additional paper supporting the significance of SIN3A: PMID: 30267900 - Narumi-Kishimoto et al. (2018), report a single individual with a frameshift mutation (p.His283fs) in the in the SIN3A gene. 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 presumably unaffected adult controls, the 15q24 LCRC-D deletion was not observed in any cases (n=29,085) or controls (n=19,584).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Duplications of this region which do not extend beyond LCRC and LCRD have not been reported. Therefore, the triplosensitivity score for this region is 0. 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 presumably unaffected adult controls, the 15q24 LCRC-D duplication was observed in 1/29,085 cases versus 0/19,584 controls (p=0.6; LR: Inf, CI: 0.364 to Inf).