ClinGen Dosage Sensitivity Curation Page

17q21.3 recurrent region (includes KANSL1)

  • Curation Status: Complete
  • id: ISCA-37420
  • Date last evaluated: 2020-08-10
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000017.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
20301783 GeneReviews article on KANSL1-related intellectual disability syndrome, including 17q21.31 deletion syndrome
18628315 Koolen et al. (2008) examined the clinical findings of 22 patients with 17q21.31 deletions. The clinical findings observed in these patients included developmental delay, hypotonia, craniofacial abnormalities, cryptorchidism, friendly/amiable behavior, seizures, pectus excavatum, scoliosis/kyphosis, cardiac defects (VSD/ASD), kidney/urologic anomalies, and additional clinical features. Parental testing was performed in 21 of the patients, and in each case, the deletion was found to be de novo.

Haploinsufficiency phenotype comments:

Deletion of the 17q21.31 recurrent region* is associated with 17q21.31 deletion syndrome, also known as Koolen-De Vries syndrome. Features associated with 17q21.31 deletion syndrome include: developmental delay/intellectual disability, hypotonia, distinctive facial features, congenital malformations, and behavioral features (friendly, amiable, and cooperative). Other features may include: epilepsy, heart defects (ASD, VSD), kidney/urologic anomalies, and cryptorchidism in males. The penetrance of this deletion is thought to be 100%. Of note, the critical gene within this region is thought to be the chromatin modifier gene KANSL1 (OMIM: 612452). This is supported by two studies, which have identified nonsense and frameshift mutations in KANSL1 that result in a 17q21.31 microdeletion syndrome phenotype (PMID: 22544363, 26424144). *The breakpoints for this region were established using Sharp et al. 2006 (PMID: 16906162) and are meant to represent the unique sequence associated with this recurrent deletion/duplication. Note that this region is adjacent to, and distinct from, the 17q21.31q21.32 (polymorphic) region which involves the first three exons of KANSL1 (transcript: NM_001193466.1). Note: The 17q21.31 region contains a common inversion polymorphism of approximately 900 kb in populations of European ancestry. The haplotypes, H1 and H2, are known in the literature to be linked with the recurrent duplication and deletion, respectively (See Boettger et al. 2012; PMID 22751096 and Jong et al. 2012; PMID 22950410 for details). 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 patients with ID/DD, MCA, and other developmental phenotypes, deletions of the recurrent 17q21.31 region were observed in 31/29,085 patients and 0/19,584 controls (p= 1.16E-0; LR: Inf, CI: 7.51 to Inf)

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
19502243 Grisart et al. (2009), reported four patients with duplications of this region. These patients were found to present with a variety of clinical features that included: psychomotor retardation, hypotonia, hyperactivity, poor social interaction, and mild dysmorphic features. The inheritance was examined in 3 of the 4 patients, and the duplication was found to be de novo in each case.
24649381 McCormack et al. (2014), described a single patient with a duplication that encompasses this region. This patient was noted to be microcephalic, developmentally delayed, and to have mild dysmorphic features. The inheritance of this duplication was not examined.
26565673 Natacci et al. (2016) examined a family with an inherited duplication of 17q21.31. The proband was first seen at 4 years of age, where she was noted to have psychomotor retardation. Later clinical evaluations revealed that this patient was also microcephalic, overweight, and had mild craniofacial abnormalities. Subsequent genetic testing in the family demonstrated that both the mother and the maternal uncle also carried the 17q21.31 duplication. Clinical evaluation of the mother revealed that she had an OFC in the 3rd-10th centile, a mild developmental delay, poor social interactions, and anxiety. The maternal uncle was reported to have intellectual disability, behavioral issues, and mild craniofacial dysmorphisms.

Triplosensitivity phenotype comment:

A total of 10 patients with the recurrent 17q21.31 duplication have been reported in the literature (See also PMID 17576104). Clinical findings associated with the duplication of this region are highly variable, with psychomotor delay being the only phenotype consistently observed across all patients. Other variably present phenotypic features include microcephaly, behavioral disorder, poor social interaction, and variable dysmorphic features. The inheritance of this duplication was examined in six of the reported cases. Five of these cases were shown to be de novo, and one was found to be inherited from a mother who was also clinically affected. Case-control data supporting enrichment of 17q21.31 duplication in the (childhood-aged) clinical population are currently lacking (see below). Due to a relatively limited number of cases of 17q21.31 duplications in the literature, with phenotypic non-specificity/variability, and lack of supportive statistical evidence for enrichment in the clinical population, the triplosensitivity score is 1. *The breakpoints for this region were established using Sharp et al. 2006 (PMID: 16906162) and are meant to represent the unique sequence associated with this recurrent deletion/duplication. Note that this region is adjacent to, and distinct from, the 17q21.31q21.32 (polymorphic) region which involves the first three exons of KANSL1 (transcript: NM_001193466.1). Note: The 17q21.31 region contains a common inversion polymorphism of approximately 900 kb, in populations of European ancestry. The haplotypes, H1 and H2, are known in the literature to be linked with the recurrent duplication and deletion, respectively (See Boettger et al. 2012; PMID 22751096 and Jong et al. 2012; PMID 22950410 for details). Additional relevant literature is summarized below: Adult onset disease association: PMID: 27956742 Le Guennec et al. (2017) showed enrichment of the 17q12.31 duplication in their case-control study using WES data from 522 undiagnosed early-onset Alzheimer's disease (EOAD) patients and 584 controls (French ancestry; mean age of onset 55 years): 4/522 cases vs 0/584 controls (P=0.049, Fishers exact test). Enrichment statistics were also calculated using control data from studies by Coe et al. 2014 (PMID 25217958; P=1.5E-5) and the ExAC database (PMID 27533299; P=2.9E-7). Clinical evaluation of 5 carrier patients (4 index and 1 affected relative) showed a single common feature of progressive cognitive decline. In one familial case, an instance of non-segregation with disease status was documented. Recruitment of another EOAD family (reported in PMID: 27143436) with similar phenotype identified the duplication in two affected members and absence in an unaffected member. The authors propose increased gene dosage of MAPT as a contributory factor to this adult neurodegenerative disorder. 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 patients with ID/DD, MCA, and other developmental phenotypes, duplications of the recurrent 17q21.31 region were observed in 3/29,085 patients and 0/19,584 controls (p=0.2130; LR: Inf, CI: 0.356 to Inf). Animal model studies: PMID: 28704368 Arbogast et al. (2017) reported functional studies using mouse models of 17q21.31 deletion and duplication. The deletion models showed similar features of Koolen-de Vries syndrome (higher level of social interaction, lower level of recognition memory, associative learning and memory and brain malformations) and the reciprocal microduplication model resulted in a single phenotypic similarity of microcephaly (which has been reported in 50% of individuals with 17q21.3 duplication). The authors correlated the overexpression of MAPT and KANSL1 in miroduplication phenotype with the SNPs for Alzheimer?s disease near these genes in this region, which resembles the familial form of late onset Alzheimer?s disease.