ClinGen Dosage Sensitivity Curation Page

17q21.3 recurrent region (includes KANSL1)

  • Curation Status: Complete
  • id: ISCA-37420
  • Date last evaluated: 2017-09-13
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000017.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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, 17q21.31 deletions were observed in 31/29,085 patients and 0/19,584 controls (p= 1.16E-07).

Haploinsufficiency phenotype comments:

Deletion of this 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). See also PMID 20301783: GeneReviews article on KANSL1-related intellectual disability syndrome, including 17q21.31 deletion syndrome *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).

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for gain of function 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:

Due to the limited number of 17q21.31 duplication carriers in the literature, along with phenotypic variability, and lack of supportive statistical evidence for enrichment in the clinical population, the triplosensitivity score is a 2. To date, at least 10 patients with the recurrent 17q21.31 duplication have been reported in the literature (PMID: 19502243, 26565673, 24649381, 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. Additional relevant literature is summarized below: 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, 17q21.31 duplications were observed in 3/29,085 patients and 0/19,584 controls. Although this duplication was only observed in the patient population, due to its relative rarity, statistical significance for enrichment of 17q21.31 duplications amongst patients was not observed (p=0.2130). *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).