 |
3q29 recurrent region (includes DLG1) |
- 3
Haplo
Score - 1
Triplo
Score
Dosage Sensitivity Summary (Region)
Dosage ID:
ISCA-37443
Curation Status:
Complete
Issue Type:
Dosage Curation -
Region
Description:
This review refers to the 3q29 recurrent region (includes DLG1).
Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency
(3)
Triplosensitivity:
Little Evidence for Triplosensitivity
(1)
Last Evaluated:
02/18/2024
Haploinsufficiency (HI) Score Details
HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- chromosome 3q29 microdeletion syndrome Monarch
HI Evidence:
-
PUBMED:
27656750
Mulle et al. GeneReviews article.
-
PUBMED:
33564151
Sanchez Russo et al. (2021) provided detailed phenotype information on 32 individuals (including four individuals from a single family) with recurrent 3q29 deletions recruited from the 3q29 online patient registry. All participants had established clinical diagnosis of a 3q29 deletion (at least 80% overlap with the recurrent deletion) and were over the age of six. Individuals were phenotyped using standardized physical, developmental, psychiatric and neurological evaluations. Common phenotypes among carriers included gastrointestinal symptoms (81%), musculoskeletal findings (81%), intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), graphomotor weakness (78%) and congenital heart defects (25%). Additional psychiatric phenotypes included psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), attention deficit-hyperactivity disorder (63%). Inheritance information was not provided.
-
PUBMED:
25714563
Cox and Butler (2015) reported a novel patient with a de novo recurrent 3q29 deletion identified by routine clinical microarray testing and summarized clinical findings for 38 carriers of both recurrent and overlapping 3q29 deletions previously reported in the literature. Of these 39 total cases, 21 were identified via older cytogenetic techniques including karyotype and/or FISH analysis, and 18 had chromosomal microarray studies performed. The novel patient presented with features similar to those in the literature, including a history of developmental delay/intellectual disability, autism spectrum disorder, gastroesophageal reflux disorder, and dysmorphic features, consistent with the phenotype typically seen in individuals with 3q29 deletions. No significant differences were noted in the clinical features between individuals diagnosed via microarray studies and those identified using previous cytogenetic methods. Of the 32 individuals for whom inheritance information was available, 22 of the deletions were de novo and 10 were inherited. Parental phenotypes were not summarized for those inherited. Refer to original studies 18471269 (Ballif 2008), 19610115 (Digilio 2009) for further details.
HI Evidence Comments:
The recurrent 3q29 deletion is associated with a variable clinical phenotype that may include mild to moderate developmental delay/intellectual disability, speech delay, autism spectrum disorder, psychiatric disorders, microcephaly, failure to thrive and/or feeding problems in infancy that may continue into childhood, gastrointestinal disorders, ocular issues, congenital defects (including patent ductus arteriosus), and mild dysmorphic features. The majority of 3q29 deletions are de novo, although inheritance from an affected, mildly affected, or unaffected parent has been reported. Parent carriers typically present with a milder phenotype that most often includes mild dysmorphic features and/or a history of learning or language delays. Case-control comparison studies have shown enrichment of this deletion in clinical populations. Therefore, the haploinsufficiency score is 3.
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 of the 3q29 region were observed in 11/29,085 cases versus 0/19,584 controls (p=0.0035; LR Inf, 95% CI:2.21-Inf), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781.
General Population Carrier Studies:
PMID: 30767844
Kendall et al. (2019) analyzed the effect of individual recurrent CNVs on cognitive performance and general measures of functioning on 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. For the purposes of dosage curation, only measures of cognitive performance are used for evidence scoring. As fewer than five 3q29 deletion carriers were tested for one or more of the cognitive measures, this study was not included in dosage evidence scoring for this region.
Case reports:
PMID: 30885185
Khan et al. (2019) reported a three-year-old male patient with a maternally inherited atypical, nested 3q29 deletion identified by routine clinical microarray testing and summarized the literature of patients with inherited 3q29 deletions, highlighting reported increased risks for adult onset neuropsychiatric phenotypes. The patient presented with global developmental delay, anemia, and mild dysmorphic features. His mother had a history of learning disabilities.
Additional Studies:
Numerous patients with 3q29 microdeletions have been reported in the literature and many are reviewed in the literature cited above. The following is an additional but not comprehensive list of related 3q29 deletion clinical publications; 21626679 (Dasouki 2011), 20453639 (Clayton-Smith 2010), 19460468 (Li 2009), 20830797 (Quintero-Rivera 2010) 24214349 (Citta 2013), 33938623 (Mak 2021), 36566217 (Pollak 2022), 37691301 (Pollak 2023), 37354284 (Pollak 2023), and 38216835 (Pollak 2024).
Triplosensitivity (TS) Score Details
TS Score:
1
TS Evidence Strength:
Little Evidence for Triplosensitivity (Disclaimer)
TS Disease:
- chromosome 3q29 microduplication syndrome Monarch
TS Published Evidence:
-
PUBMED: 32154651
Pollak et al. (2020) surveyed 31 individuals from the 3q29 online registry using a custom medical and demographic questionnaire to perform a case-control phenotypic analysis of 3q29 duplication carriers. Common self-reported features among participants included feeding problems (55%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%), learning problems (71%), seizures (26%), and self-reported autism spectrum disorder diagnoses (39%). Inheritance information was not provided.
-
PUBMED: 33039685
Coyan et al. (2020) described 11 patients from 9 families with 3q29 duplications identified by microarray, ranging from atypical, smaller duplications to the typical, recurrent 3q29 duplication. Phenotypes of patients previously reported in the literature were also summarized. Common findings in this cohort included developmental delay/intellectual disability, speech delay, and dysmorphic features. Other findings included musculoskeletal anomalies, seizures, microcephaly, and obesity. In the 9 families with the recurrent duplication, 1/9 was de novo and 8/9 had unknown inheritance. In one family, a 2p11.2 deletion was also identified but was not expected to have contributed to the clinical phenotype. In the 2 families with smaller, atypical duplications in which the minimal region of overlap with the recurrent 3q29 duplication included only the BDH1 gene, one duplication was inherited from an unaffected mother and the other had unknown inheritance. A 17q12 duplication involving a neuro-susceptibility locus with overlapping phenotypes was also identified in one proband and was thought to have contributed to the more severe phenotype reported in this patient.
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PUBMED: 29501613
Tassano et al. (2018) reported 2 new patients (referred for clinical microarray) and provided a review of 10 previously reported cases with the recurrent 3q29 duplication. Patient 1 had a 3q29 duplication that was slightly larger than the typical recurrent duplication and presented with developmental delay/intellectual disability, behavioral problems, autism, hypotonia, and gait abnormalities. The inheritance was unknown. Patient 2 had a smaller, nested, maternally inherited 3q29 duplication encompassing only the genes DLG1 and BDH1. She presented with developmental delay/intellectual disability, growth failure, hypotonia, gait abnormalities, and seizures. Maternal clinical information was not provided.
-
PUBMED: 18471269
Ballif et al. (2008) identified 5 individuals with the recurrent 3q29 duplication from a cohort of 14,698 individuals with intellectual disability who had clinical (low resolution) microarray analysis. Clinical information was only available for 3 of these individuals, all of whom displayed mild to moderate intellectual disability. Additional clinical findings included obesity, macrocephaly, microcephaly, VSD, craniosynostosis, and other mild dysmorphic features. Three cases were inherited, two were unknown. For inherited cases, clinical information was unavailable for carrier parents.
TS Evidence Comments:
Evidence in support of the pathogenicity of recurrent 3q29 duplication is limited at this time. Although there are numerous carriers of this CNV reported in the literature, the number of independent studies are still somewhat limited and phenotypes documented across them are variable, relatively nonspecific, and sometimes inconsistent. Phenotypes reported consistently amongst affected 3q29 duplication carriers in the clinical population include developmental delay/intellectual disability, autism spectrum disorders, speech delay, hypotonia, growth delay, obesity, seizures, gait abnormalities, and craniofacial dysmorphisms. Inheritance information for 3q29 duplications is overall limited at this time. Available case-control comparison studies have not shown enrichment of this duplication in clinical populations though numbers were relatively low. 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 3q29 region were observed in 6/29,085 cases versus 2/19,584 controls (p=0.31; LR: 2.02, 95% CI: 0.425-12.2), demonstrating insufficient evidence for enrichment of this CNV in the clinical population. See also Cooper et al. (2011) PMID 21841781.
Case Reports:
PMID: 18241066
Lisi et al. (2008) reported 5 individuals from a three-generation family with the recurrent 3q29 duplication. The duplication was initially identified by chromosome analysis, and further characterized by BAC a-CGH, FISH and SNP analysis. Individuals who carried the duplication included male and female siblings, their mother (the proband), a maternal aunt, and a maternal grandfather, all of whom, except for the grandfather, presented with mild to moderate intellectual disability, obesity, dysmorphic features, and microcephaly. The grandfather had a history of dysmorphic features and required special education as a child. Eight other CNVs of unknown significance found to be segregating in the family, ranged from 10-500 kb. The authors indicated that the 3q29 duplication was the only significant chromosomal imbalance that segregated with the phenotype.
PMID: 36691815
Bauleo et al. (2023) reported a two-generation family with a smaller, atypical 3q29 duplication encompassing only the genes DLG1 and BDH1. The duplication was identified in a four year-old proband and two year old brother (with developmental delay/intellectual disability, speech delay, learning disabilities. The proband also presented with autism/stereotypical behaviors. The duplication was identified in an unaffected sister and mother. The proband also carried an intragenic duplication involving the gene CNTN5, which was inherited from an unaffected father and classified as a variant of uncertain significance.
PMID: 32874693
Streata et al. (2020) provided a case report of a patient with the recurrent 3q29 duplication identified by clinical genomic microarray. She had normal cognitive and motor development until age 10, at which point she developed attention deficit disorder, hyperkinesia, gait difficulties, and abnormal coordination. She further developed psychomotor delay, intellectual disability, behavioral abnormalities, speech impairment, dysphagia, and chronic pain. At age 34, the patient was non-ambulatory and presented with balance problems, brain anomalies, and dysmorphic features. Inheritance was unknown.
PMID: 24838842
Fernandez-Jaen et al. (2014) described a patient with a de novo 3q29 duplication identified by routine clinical microarray testing. The patient presented with developmental delay/ severe intellectual disability, epilepsy, cerebral palsy, and dysmorphic features.
Genomic View
Select assembly:
(NC_000003.11)
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