ClinGen Dosage Sensitivity Curation Page

13q12.12 recurrent region (includes SACS and SGCG)

  • Curation Status: Complete
  • id: ISCA-46298
  • Date last evaluated: 2021-04-26
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: Triplosensitivity unlikely


Location Information

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Evidence for haploinsufficiency phenotype
PubMed ID Description
30767844 Kendall et al. (2019) analyzed the effect of the 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.

Haploinsufficiency phenotype 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. Recent studies of deletion carriers identified through cohort studies on the general population have also shown that carrier individuals perform similarly to non-carrier controls on neurocognitive tests. Therefore, the haploinsufficiency score for this region is 0*. Deletion of the 13q12.12 region has been reported in association with autosomal recessive phenotypes due to bi-allelic loss-of-function variants involving genes within the deleted interval, including spastic ataxia of the Charlevoix-Saguenay type (OMIM: 270550, due to the gene SACS) and combined oxidative phosphorylation deficiency-3 (OMIM: 617228, due to the gene MIPEP). The gene SGCG, associated with recessive limb-girdle muscular dystrophy (OMIM: 253700), also resides in this deleted interval. *Due to the presence of multiple genes within this region it is scored as a whole instead of at the gene level. Therefore, despite the presence of multiple recessive genes it is scored as "0" instead of "30-gene associated with a recessive phenotype." 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 score: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely

Triplosensitivity phenotype comment:

Duplication of the 13q12.12 region currently has evidence refuting its significance. Duplications of this region are observed at similar frequencies in both cases and controls and are not enriched in the clinical population. Recent studies of duplication carriers identified through cohort studies on the general population have also shown that carrier individuals perform similarly to non-carrier controls on neurocognitive tests. Therefore, the triplosensitivity score for this region is Dosage Sensitivity Unlikely. 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. PMID: 23239789 McElroy et al. (2013), report a single patient with a 13q12.12 duplication. This patient was identified as part of a retrospective study aimed at identifying copy number variants associated with pediatric multiple sclerosis patients. The clinical findings reported in this patient include hand tremor, clumsiness, balance problems, learning difficulty, dyslexia, neuropathy, and white matter lesions by MRI. Inheritance testing using comparative genomic hybridization demonstrated that duplication was de novo.