 |
13q12.12 recurrent region (includes SACS, SGCG) |
- 0
Haplo
Score - 0
Triplo
Score
Dosage Sensitivity Summary (Region)
Dosage ID:
ISCA-46298
Curation Status:
Complete
Issue Type:
Dosage Curation -
Region
Description:
This review refers to the 13q12.12 recurrent region (includes SACS, SGCG).
Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
No Evidence for Haploinsufficiency
(0)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Last Evaluated:
04/18/2024
Haploinsufficiency (HI) Score Details
HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency
(Disclaimer)
HI Evidence:
-
PUBMED:
30767844
Kendall et al. (2019) analyzed the effect of the recurrent ~1.4Mb 13q12.12 deletion on cognitive performance and general measures of functioning of 84 deletion carrier adults recruited from the UK Biobank cohort (a large, genotyped population) compared to non-carrier controls from the same population. Significant differences were observed for 2 of 11 total measurements (average effect size: -0.16), including 1 of 7 cognitive measures and 1 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this deletion was estimated to be 4% using a previously reported clinical cohort compared to the UK Biobank control database.
HI Evidence Comments:
There is currently insufficient evidence to support 13q12.12 haploinsufficiency. This deletion has not been reported in association with a dominant phenotype (see information on recessive disease associations below) and deletions of this region are not enriched in the clinical population. Cohort studies of the general population have also shown that deletion carrier individuals perform similarly to non-carrier controls on neurocognitive tests. Taken together, the haploinsufficiency score for this region is 0.
Additional relevant literature is summarized below:
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 controls, deletions of the recurrent 13q12.12 region were observed in 5/29,085 cases versus 1/19,584 controls (p=0.2296; LR=3.37 (0.453 to 51.5)), demonstrating a lack of enrichment in the clinical population.
Reports of recessive disease association:
PMID: 30498468
Dougherty et al. (2018): Report a single patient with a deletion of this region. The patient was also reported to have a pathogenic frameshift variant in SACS (c.11824dup) and was diagnosed with autosomal recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). Parental testing was not performed to see if the 13q12.12 deletion was inherited or de novo.
PMID: 18398442
Breckpot et al. (2008): Report a single patient with a de novo deletion of this region. The patient was also reported to have a hemizygous missense variant in SACS (c.10517T>C) and was diagnosed with ARSACS.
PMID: 19031088
Terracciano et al. (2009): Report a two patients with deletions of this region. Both patients were found to carry hemizygous variants in SACS and had clinical features of ARSACS. Parental testing was performed on one of the patients, and the deletion was found to be maternally inherited.
PMID: 27799064
Eldomery et al. (2016): Report a single patient with deletion of this region. The patient was also found to have a hemizygous missense variant in MIPEP (p.H512D), and presented with seizures, dysmorphic features, ventricular hypertrophic cardiomyopathy, lactic acidosis and ketosis, and additional clinical findings. The patient was noted to have died at 19 days of life. Parental testing showed that the deletion was maternally inherited.
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
There is currently insufficient evidence to support triplosensitivity of the 13q12.12 region. Although a single case in the literature describes a de novo duplication in an affected individual, duplications of this region are observed at similar frequencies in both cases and controls and are not enriched in clinical populations. Cohort studies of the general population have also shown that duplication carriers perform similarly to non-carrier controls on neurocognitive tests. Taken together, the triplosensitivity score for this region is 0.
Additional relevant literature is summarized below:
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 controls, duplications of the recurrent 13q12.12 region were observed in 9/29,085 cases versus 12/19,584 controls (p=0.68; LR=0.505 (0.214 to 1.17)), demonstrating a lack of enrichment in the clinical population.
Additional Cohort Studies:
PMID: 30767844
Kendall et al. (2019) analyzed the effect of the 13q12.12 duplication on cognitive performance and general measures of functioning of 233 duplication carrier adults recruited from the UK Biobank cohort (a large, genotyped population) compared to non-carrier controls from the same population. Significant differences were observed for 0 of 11 total measurements (average effect size: -0.01). Penetrance for any clinical phenotype associated with this duplication was estimated to be 3% using a previously reported clinical cohort compared to the UK Biobank control database; however given the conflicting performance data, the significance of this estimate is uncertain.
Additional Case Reports
PMID: 23239789
McElroy et al. (2013), investigated CNVs in a trio-based aCGH study of 30 pediatric patients with multiple sclerosis, and reported a single patient with a de novo 13q12.12 duplication. The clinical findings reported in this patient include hand tremor, clumsiness, balance problems, learning difficulty, dyslexia, neuropathy, and white matter lesions by MRI. All other CNVs identified in this study were found in DGV and inherited, so presumed to be benign. The authors note that the 13q12.12 duplication was likely not causative of the patient's MS phenotype but may have contributed to other clinical features. No functional studies were performed to confirm or refute this hypothesis.
