10q11.2 recurrent region (LCR C-LCR D)

  • 1
    Haplo
    Score
  • 1
    Triplo
    Score

Region Facts

Region Name
10q11.2 recurrent region (LCR C-LCR D)
Cytoband
10q11.22-q11.23
Genomic Coordinates
GRCh37/hg19 chr10:49389703-51053583 NCBI Ensembl UCSC
GRCh38/hg38 chr10:48181660-49845537 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37497
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
The 10q11.2 recurrent region contains clusters of low-copy repeats (LCRs) that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to recurrent copy number variants (CNVs) encompassing the nested LCR-C to LCR-D region (10q11.2 LCR-C-D). Larger CNVs extending into LCR-A through LCR-F are considered functionally similar to LCR-C-D CNVs and are included in this review. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
Little Evidence for Triplosensitivity (1)
Last Evaluated:
10/12/2022

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 21948486
    Stankiewicz et al. (2012) report 23 individuals with deletions overlapping the 10q11.2 recurrent LCR-C-D region from a clinical population referred for genomic microarray testing. The majority of patients with the 10q11.2 recurrent deletion were reported to have developmental delay or intellectual disability. The additional clinical findings were variable and included behavioral differences (attention deficit hyperactivity disorder, autism spectrum disorder), mild dysmorphic craniofacial findings, and seizures. A subset of patients (9 of 23) carried additional CNVs, including an ~12 Mb deletion on 3q, an ~4.8 Mb duplication on 12q, and an ~11.4 Mb duplication of 6q, which likely contributed to the phenotype. Parental testing was performed for 14 of the reported recurrent deletions, with 12 being inherited from a carrier parent and 2 being de novo. Ten of the carrier parents and 1 carrier grandparent was apparently unaffected. Whereas 1 carrier parent and 1 carrier sibling (both from the same family, carrying a concurrent 4.8 Mb duplication on 12q) were reportedly affected. Comparison of the relative frequency of deletion carriers within their clinical cohort (21/58,175 cases) versus controls (0/9,183 individuals) found that the deletions were nominally enriched in the clinical population (p=0.046, Fisher Exact test). However, the authors noted the potential for bias of ascertainment due to the selection of these individuals from a population referred for microarray testing.
  • PUBMED: 20466309
    Chen et al. (2010) reported a fetus with a de novo 10q11.2 LCR-A-D deletion. The reported phenotypes included facial dysmorphism (hypotelorism, micrognathia, large, low-set ears). The fetus was terminated at 24 weeks gestation. No other copy number changes were reported.
  • PUBMED: 17531565
    Bisgaard et al. (2007) reported a female patient with a maternally inherited 10q11.2 LCR-A-E deletion. No other copy number changes were reported. The features reported in the proband included developmental delay, microcephaly, central and cortical atrophy on MRI, various dysmorphisms, and frequent infections of the upper airways. The carrier mother (characterized by array) and two carrier sisters (characterized by chromosome analysis) were reported to be healthy. The deletion was classified as a likely incidental, non-contributory finding.
HI Evidence Comments:
Evidence in support of the pathogenicity of the 10q11.2 recurrent region (LCR-C to LCR-D) deletion is limited at this time. Deletions of this region are relatively rare in the literature, with 25 independent cases reported across three studies. Amongst affected carriers, clinical findings are mostly nonspecific, including developmental delay, intellectual disability, behavioral differences, mild dysmorphism, seizures, and other variable findings. The reported deletions are typically inherited and, where studied, often from apparently healthy parents. A subset of patients have additional CNVs that are likely contributing to their reported clinical presentation. Furthermore, case-control comparison studies have not consistently shown enrichment of deletions involving this region in the clinical population (PMID: 25217958; 21948486). Due to the limited number of reported cases, non-specific clinical presentation, lack of consistent enrichment in case control studies, and the deletion often being inherited from an unaffected parent, the haploinsufficiency score is 1. Additional relevant literature is summarized below: Case-Control Studies: PMID: 25217958 Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Deletions overlapping the 10q11.2 LCR-C-D region were observed in 8/29,085 cases versus 4/19,584 controls (p=0.4314; LR: 1.35, 95% CI: 0.412-4.72), with no evidence of enrichment of this CNV in the clinical population. General Population Carrier Studies: PMID: 30767844 Kendall et al. (2019) analyzed the effect of the 10q11.2 LCR-C-D deletion on cognitive performance and general measures of functioning of 57 deletion carrier adults recruited from the UK Biobank cohort (a large, genotyped group from the general population) compared to non-carrier controls from the same population. Significant differences were observed for 4 of 11 total measurements, including 0 of 7 cognitive measures and 4 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this deletion was estimated to be 7% using a previously reported clinical cohort compared to the UK Biobank control database. Carrier Parents of Child Affected with Autosomal Recessive Disorder for Genes in the Interval: CHAT – autosomal recessive congenital myasthenic syndrome PMID: 29130637 Schwartz et al. (2018) reported a maternally-inherited 10q11.2 LCR-A-E deletion together with a hemizygous, paternally-inherited, CHAT splicing variant (Patient 1). The patient presented with respiratory problems, seizure-like episodes, muscle weakness, ptosis, developmental delay, and additional clinical findings, consistent with congenital myasthenic syndrome. The carrier mother was reported to be healthy. ERCC6 – Cerebrooculofacioskeletal syndrome 1, Cockayne syndrome, type B, De Sanctis-Cacchione syndrome, UV-sensitive syndrome 1 PMID: 21376145 Ghai et al. (2011) reported a paternally inherited 10q11.2 LCR-B-E deletion together with a maternally inherited ERCC6 frameshift variant. The patient presented with microcephaly, global developmental delay, brain atrophy on CT scan and additional clinical findings, consistent with severe infantile Cockayne syndrome. The father was reported to be healthy.

Triplosensitivity (TS) Score Details

TS Score:
1
TS Evidence Strength:
Little Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 21948486
    Stankiewicz et al. (2011) report 13 individuals from a clinical population referred for genomic microarray testing with recurrent duplications overlapping the 10q11.2-LCR-C-D region. Patients with non-LCR mediated duplications overlapping this region were not included (patients 27, 31, 34, 37). Limited clinical information was available on these patients; however, the indication for testing for most patients included developmental delay/intellectual disability. Additional clinical features reported in at least two of these patients include autism spectrum disorder, seizures, dysmorphic features, and multiple congenital anomalies. Seven of the duplications represented inherited events and none were reported to be de novo. Parental phenotype information was not reported. A subset of patients (3 of 13) carried additional copy number variants, including 1 patient with a deletion of SHOX. Comparison of the relative frequency of duplication carriers within the clinical population (12/58,175 cases) versus controls (0/9,183 individuals) did not reveal a significant difference in the prevalence of duplications between these populations (p=0.17, Fisher Exact test).
  • PUBMED: 24669257
    Manolakos et al. (2014) report a single patient with a de novo duplication encompassing the 10q11.2 LCR-A-E region. The patient presented with hypotonia, ataxia, mild dysmorphic features, hypoplasia of the corpus callosum, developmental delay, pectus carinatum, and additional clinical findings. The reported craniofacial findings included triangular face, frontal, bossing, and micrognathia.
  • PUBMED: 28846756
    Borlot et al. (2017) report a set of monozygotic twins with a de novo duplication of the 10q11.2 LCR-C-D region who were recruited from an epilepsy outpatient clinic. The patients presented with intellectual disability, autistic features, seizures, short stature, and microcephaly.
  • PUBMED: 34207052
    Tritto et al. (2021) report 1 patient with a maternally inherited duplication encompassing the 10q11.2 LCR-C-D region. The patient presented with intellectual disability, autism spectrum disorder, developmental delay, and hypotonia. The carrier mother was unaffected.
TS Evidence Comments:
Evidence in support of the pathogenicity of recurrent 10q11.2 LCR-C-D duplication is limited at this time. Duplications of this region are rare in the literature, with 16 independent cases reported across 4 studies. Amongst affected carriers, clinical findings are mostly nonspecific, including developmental delay, intellectual disability, and other variable findings. Due to the limited number of reported cases with variable inheritance and lack of parental phenotype information, inheritance and penetrance are not well-understood. Case-control comparison studies have not shown consistent enrichment of this duplication in clinical populations. Therefore, the triplosensitivity score is 1. Additional literature is summarized below: Case-Control Studies PMID: 25217958 Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Duplications of the 10q11.2 LCR-C-D region were observed in 7/29,085 cases versus 0/19,584 controls (p=0.02721; LR: Inf, 95% CI: 1.23-Inf), demonstrating nominal enrichment of this CNV in the clinical population. General Population Carrier Studies: PMID: 30767844 Kendall et al. (2019) analyzed the effect of the 10q11.2 LCR-C-D duplication on cognitive performance and general measures of functioning of 41 duplication carrier adults recruited from the UK Biobank cohort (a large, genotyped group from the general population) compared to non-carrier controls from the same population. Significant differences were observed for 0 of 11 total measurements, including 0 of 7 cognitive measures and 0 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this duplication was estimated to be 11% using a previously reported clinical cohort compared to the UK Biobank control database.

Genomic View

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