ClinGen Dosage Sensitivity Curation Page

15q24 recurrent region (A-C)

  • Curation Status: Complete
  • id: ISCA-46296
  • Date last evaluated: 2020-01-03
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

  • 15q24.1-q24.2
  • GRCh37/hg19 chr15: 72,963,715-75,508,312
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr15: 72,671,374-75,215,971
  • View: NCBI | Ensembl | UCSC
Select assembly: () ()
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22180641 Mefford et al. (2012) reported four patients (Patients 2-5) with 15q24 LCRA-C deletions. These patients presented with developmental delays (including motor and speech), intellectual disability, craniofacial dysmorphisms, ocular anomalies, ear anomalies (including infections and hearing loss), hypotonia, abnormal behaviors, variable skeletal and skin anomalies, and additional variable clinical findings. Inheritance testing was completed in three of the four patients, and in each case the deletion was found to be de novo.
19921647 Andrieux et al. (2009) reported a single patient (Patient 3) with a 15q24 LCRA-C deletion. This patient presented with developmental delay (speech and motor), hypoplastic olfactory bulbs by MRI, ocular anomalies, hearing loss, asymmetric dysplastic ears, thin upper lip, widely spaced teeth, tetralogy of Fallot, and dry skin. Parental testing showed that this deletion was de novo.

Haploinsufficiency phenotype comments:

Deletion of the 15q24 recurrent region (A-C)* ** has been reported in at least 5 patients in association with a clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features. In all cases where parental studies have been performed, deletions were 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). The region between 15q24 LCRB-C (~1.1 Mb) has been proposed to be a critical deleted interval within this region (PMID: 22359776, 25217958). 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 causative of the complete phenotype(s) associated with the region. **Note - Deletions involving the 15q24A-D region are covered in a separate region review. Additional relevant literature is summarized below: Reviews: PMID 22359776: GeneReviews. Mefford, Shur, Rosenfeld. PMID 22216833: Chromosome 15q24 microdeletion syndrome. Magoulas and El-Hattab (2012). 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 LCRA-C deletion was observed in 7/29,085 cases versus 0/19,584 controls (p=0.027; LR: Inf, CI: 1.23 to Inf), providing evidence for enrichment of this deletion in the clinical population.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
19557438 El-Hattab et al. (2009) reported a single patient (Case 5) with a 15q24 LCRA-C duplication. This patient presented with short stature, mild intellectual disability, hypertonia, craniofacial abnormalities, decreased joint range of motion, digital anomalies, and behavioral abnormalities. The reported craniofacial features included a long face, down-slanting palpebral fissures, puffy eyelids, ptosis, smooth philtrum, and retrognathia. Maternal testing for this duplication was negative, but the father was not available for inheritance testing.
20860070 El-Hattab et al. (2010) reported a single patient with a 15q24 LCRA-C duplication, as well as a maternally inherited 2.4 Mb 16q22 duplication. The patient died in infancy, and had IUGR, FTT, craniofacial abnormalities (flat philtrum and puffy eyelids), cardiac anomalies (ASD, VSD, PDA, PS, and dextrocardia), heterotaxy, gastrointestinal obstruction, hydronephrosis, and additional clinical findings. The 15q24 LCRA-C duplication was paternally inherited; the patient?s father was reported to have congenital heart disease.

Triplosensitivity phenotype comment:

Duplication of the 15q24 recurrent region (A-C)* has been reported in two patients (from two families) with variable clinical findings. In addition, one patient with a duplication partially overlapping this region (B-D) has also been reported (summarized below). Due to the limited number of reported cases involving this region, phenotypic variability, evidence for reduced penetrance from parental studies in one case, and insufficient significance estimates from case-control studies (due to a limited number of observations), the current triplosensitivity score is 1. *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 causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: PMID 18755302 Kiholm Lund et al. (2008) reported a single patient with a 15q24 LCRB-D duplication. This patient presented with global developmental delay (speech and motor), abnormal MRI findings (agenesis of the corpus callosum, dilation of the lateral ventricles, and a small hemorrhage of the left parital region), hypertonia, craniofacial dysmorphisms, digital anomalies, hypospadias, eye anomalies, ear infections, and additional minor phenotypic features. The duplication was inherited from the father, who was reportedly unaffected. 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 LCRA-C duplication was observed in 3/29,085 cases versus 0/19,584 controls (p=0.2130; LR: Inf, CI: 0.356 to Inf).