ClinGen Dosage Sensitivity Curation Page

3q29 recurrent region (includes DLG1)

  • Curation Status: Complete
  • id: ISCA-37443
  • Date last evaluated: 2016-01-21
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000003.11) ()

Haploinsufficiency phenotype comments:

At this time there is sufficient evidence to support the haploinsufficiency of the ~1.6 Mb 3q29 microdeletion region. Greater than 30 patients with 3q29 microdeletions have been reported in the literature (see PMIDs 25714563, 21626679, 20453639, 19460468). 3q29 deletion is associated with a variable clinical phenotype that may include mild to moderate developmental delay, intellectual disability, autism spectrum disorder, speech delay, delayed walking, microcephaly, and mild dysmorphic features. (Quintero-Rivera et al. 2010; PMID 20830797 and Citta et al. 2012; PMID 4214349). Parental studies have shown the majority of 3q29 deletions occurred de novo, however inheritance from affected parents has also been reported (PMIDs 18471269, 19460468, and 19610115). 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, 3q29 deletions were observed in 11/29,085 cases versus 0/19,584 controls (p=0.0035) (Coe et al. 2014; PMID 25217958 and Cooper et al. 2011; PMID 21841781). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region.

Evidence for triplosensitivity phenotype
PubMed ID Description
18241066 In Lisi et al. (2008), the authors describe a three generation family in which five patients were found to carry a duplication of the 3q29 region. Patients with this duplication were found to present with intellectual disability, microcephaly, obesity, and other mild dysmorphic features.
18471269 In Ballif et al. (2008), the authors identify 5 individuals with 3q29 duplications that represent the reciprocal of the 3q29 microdeletion syndrome. Clinical information was only available for three of these patients, all of which displayed mild to moderate intellectual disability. Additional phenotypes that were seen in patients included obesity, macrocephaly, microcephaly, VSD, craniosynostosis, and other mild dysmorphic features. Three of the five patients with 3q29 duplications had inherited it from a parent; however, there was no clinical information available for the parents.
24838842 In Fernandez-Jean et al. (2014), the authors identify an additional patient with the 3q29 microduplication. This patient presented with severe intellectual disability, obesity, congenital heart defect, and other mild dysmorphic features. The duplication in this patient was de novo.

Triplosensitivity phenotype comment:

At this time there are 10 patients with 3q29 duplications that are reported in the literature. The most common phenotypes associated with duplications of this region include intellectual disability, microcephaly, obesity, cardiac anomalies, and high palate (Fernandez-Jean 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, 3q29 duplications were observed in 6/29,085 cases versus 2/19,584 controls (p=0.31) (Coe et al. 2014; PMID 25217958 and Cooper et al. 2011; PMID 21841781). Even though there are a number of cases reported in the literature, large-scale comparisons between cases and controls do not reveal a statistically significant excess of duplications amongst cases; because of this, the triplosensitivity score is 2. More phenotypic studies are needed to understand the clinical significance of 3q29 duplications. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region.