ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37396
  • Date last evaluated: 2018-08-31
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

  • 15q24.1-q24.2
  • GRCh37/hg19 chr15: 72,963,715-75,972,909
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr15: 72,671,374-75,680,568
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000015.9) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
22180641 Mefford et al. (2012) reported four patients (Patients 6-9) with 15q24 LCRA-D deletions. Clinical findings in common included growth delay/short stature, developmental delays (including motor and speech), intellectual disability, craniofacial dysmorphisms, ocular anomalies, hearing loss and/or ear infections/anomalies, hypotonia, variable skeletal anomalies, and additional variable clinical findings. Inheritance was de novo in three cases and unknown in one case (patient 6).
19557438 El-Hattab et al. (2009) reported two patients (Cases 3 and 4) with 15q24 LCRA-D deletions. Clinical findings in common included developmental delay/intellectual disability, mild and variable craniofacial anomalies, hypotonia, genital anomalies, skeletal anomalies (including joint laxity and digital anomalies), recurrent ear infections, skin findings, and other variable findings. Inheritance was de novo for both cases.
19233321 Van Esch et al. (2009) describe a single patient with a 15q24 LCRA-D deletion. This patient presented with developmental delay (speech and motor), intellectual disability, craniofacial abnormalities, hypotonia, scoliosis, talipes equinovarus (club foot), diaphragmatic hernia, digital anomalies, genital abnormalities, and behavioral problems. Inheritance was de novo.

Haploinsufficiency phenotype comments:

Deletion of the 15q24 LCRA-D region* (~3.1 Mb) has been reported in at least 10 patients in association with a syndromic clinical phenotype characterized by growth delays, developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypotonia, joint laxity, ocular abnormalities, digital findings, genital abnormalities, 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 and LCRC (1.1 Mb) has been proposed to be a critical deleted interval within this region (PMID: 22359776, 25217958). However, a recent study has found that the region between 15q24 LCRC and LCRD (encompassing SIN3A) is also associated with an abnormal phenotype when deleted (PMID: 27399968). 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 also 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: Reviews: PMID 22359776: GeneReviews. Mefford, Shur, Rosenfeld. PMID 22216833: Chromosome 15q24 microdeletion syndrome. Magoulas and El-Hattab (2012). Additional case reports: PMID 19921647: Andrieux et al., 2009 (Patients 2 and 4, both de novo) PMID 19533778: Masurel-Paulet et al., 2009 (one patient, de novo) Reports of cases overlapping (contained within) this region: PMID: 27399968: Witteveen et al. (2016), report 4 patients with deletions in the 15q24 LCRC-D region. These patients presented with intellectual disability, abnormal brain MRIs, thin hair, dysmorphic craniofacial features, and additional clinical findings. Parental testing showed that each of these deletions was de novo. The authors also report multiple patients with loss-of-function type mutations 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. 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-D deletion was observed in 2/29,085 cases versus 0/19,584 controls (p=0.3570; LR: Inf, CI: 0.175 to Inf). Of note, the 15q24 LCRA-C and LCRC-D deletions were each observed in 7/29,085 cases versus 0/19,584 controls (p=0.027; LR: Inf, CI: 1.23 to Inf), suggesting the lack of enrichment of 15q24 LCRA-D deletions may be due to their relative rarity.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Duplication of the 15q24 LCRA-D region* (~3.1 Mb) has not yet been reported. However at least three patients with recurrent duplications contained by this region (either LCRA-C or LCRB-D) have been reported (summarized below). Clinical findings observed amongst these patients are variable, with developmental delays, hypertonia, and craniofacial abnormalities reported in at least two individuals. Parental studies were performed in two of the three cases, and demonstrated parental inheritance in both cases. Due to the limited number of reported cases involving this region, phenotypic variability, emerging evidence for reduced penetrance from parental studies, 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 also that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Additional relevant literature is summarized below: Reports of cases overlapping (contained within) this region: PMID 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. Inheritance of this duplication was unknown (maternal testing negative). PMID 20860070: El-Hattab et al. (2010) reported a single patient with a 15q24 LCRA-C duplication, as well as another large unrelated CNV (16q22 duplication (~2.4 Mb), maternally inherited). The patient died in infancy, and had IUGR, FTT, craniofacial abnormalities, cardiac anomalies (ASD, VSD, PDA, PS, and dextrocardia), heterotaxy, gastrointestinal obstruction, and hydronephrosis. Inheritance for the 15q24 LCRA-C duplication was paternal; the patient?s father was reported to have congenital heart disease. 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-D duplication was observed in 3/29,085 cases versus 0/19,584 controls (p=0.2130; LR: Inf, CI: 0.356 to Inf). Note that combining data for duplications intersecting the reciprocal of the proposed critical region (B-C) yielded 7 case vs 0 control duplications (p=0.027; LR: Inf, CI: 1.23 to Inf) (see Supplementary Table 2). NOTE: This review covers the majority of the 15q24 duplications reported in the literature; however, two patients have also been reported to have a non-overlapping duplication that involves the 15q24 LCRD-E region (El-Hattab et al., 2009; PMID 19557438).