Submission Details

DPP6 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2013 (PMID: 23832105). Since that time, numerous variants have been reported in this gene in individuals with seemingly disparate phenotypes, inherited from reportedly unaffected parents, or observed in control populations. Further, population data from gnomAD (v2.1.1) indicates that DPP6 is not highly constrained for either protein truncating variants (pLI = 0.34) or missense variation (Z score = 2.24), calling into question the relevance of previously reported variants in affected individuals. A detailed summary of available evidence and rationale for disputing this gene-disease relationship is provided below.

In the initial report by Liao et al. (PMID: 23832105) copy number variation (CNV) analysis of 22 patients with microcephaly and variable intellectual disability (ID) identified two de novo deletions in DPP6, both overlapping exon 1 (NM_130797). The same study sequenced DPP6 in 50 additional patients with microcephaly and detected a missense variant in a three-generation pedigree with four affected individuals with microcephaly and ID. Functional studies of this missense variant and additional testing to rule out other possible genetic causes were not performed. Given the lack of evidence supporting their role in disease and the fact that no other DPP6 variants have been reported in association with microcephaly and ID, these variants were not scored.

Rare deletions in DPP6 have been reported in individuals with other neurodevelopmental and neuropsychiatric phenotypes, but their pathogenicity is also unclear. Three deletions were detected in individuals with autism spectrum disorder (one de novo, two inherited; PMIDs: 18252227, 20531469, 26402605). Of note, the patient with the de novo deletion did not have microcephaly (PMID: 20531469). Note that due to limitations of the ClinGen Gene Curation Interface, large deletions are unable to be scored at this time. Deletions were also identified in a family with Tourette syndrome (PMID: 25129042), an individual with attention-deficit hyperactivity disorder (inherited; PMID: 19546859), and an individual with schizophrenia (inheritance unknown; PMID: 30208311). In addition, disruption of DPP6 has been reported in association with other phenotypes, including a chromosomal inversion disrupting DPP6 in a three-generation pedigree with autosomal dominant Alzheimer’s disease (PMID: 30874922), and a translocation disrupting DPP6 in an otherwise healthy male with azoospermia and in his mother and sister with normal phenotype (PMID: 24937803).

With respect to sequence variants, five nonsense variants, including one de novo and four without inheritance information, were identified in exome studies of autism spectrum disorder (PMIDs: 31452935, 31981491). Protein truncating variants have also been reported in an individual with schizophrenia (PMID: 27694994), two individuals with frontotemporal dementia (PMID: 30874922), and two parents of patients with autism (PMID: 31981491), but also in 50 subjects in gnomAD.

Taken together, the available genetic evidence fails to support a role for heterozygous disruption of DPP6 in ID, autism or other neurodevelopmental disorders. DPP6 encodes an auxiliary subunit of Kv4.2 potassium channels. Dpp6 knockout mice exhibit impaired hippocampal synaptic development and function, learning and memory deficits, and reduced body and brain weight (PMIDs: 21943606, 23912628, 29651237). The effects of heterozygous loss of Dpp6 were not examined in these studies. Due to the limited human genetic evidence for DPP6, the experimental evidence was not scored.

In summary, the evidence supporting the relationship between DPP6 and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 5, 2021 (SOP Version 8).

The relationship between variants in DPP6 and autosomal dominant complex neurodevelopmental disorder was first reported in 2013. Since that time, numerous variants have been reported in this gene in individuals with seemingly disparate phenotypes, inherited from reportedly unaffected parents, or observed in control populations. Further, population data from gnomAD (v2.1.1) indicates that DPP6 is not highly constrained for either protein truncating variants (pLI = 0.34) or missense variation (Z score = 2.24), calling into question the relevance of previously reported variants in affected individuals. A detailed summary of available evidence and rationale for disputing this gene-disease relationship is provided below.

In the initial report by Liao et al. (PMID: 23832105) copy number variation (CNV) analysis of 22 patients with microcephaly and variable intellectual disability (ID) identified two de novo deletions in DPP6, both overlapping exon 1 (NM_130797). The same study sequenced DPP6 in 50 additional patients with microcephaly and detected a missense variant in a three-generation pedigree with four affected individuals with microcephaly and ID. Functional studies of this missense variant and additional testing to rule out other possible genetic causes were not performed. Given the lack of evidence supporting their role in disease and the fact that no other DPP6 variants have been reported in association with microcephaly and ID, these variants were not scored.

Rare deletions in DPP6 have been reported in individuals with other neurodevelopmental and neuropsychiatric phenotypes, but their pathogenicity is also unclear. Three deletions were detected in individuals with autism spectrum disorder (one de novo, two inherited; PMIDs: 18252227, 20531469, 26402605). Of note, the patient with the de novo deletion did not have microcephaly (PMID: 20531469). Please note that due to limitations of the Gene Curation Interface, large deletions are unable to be scored. Deletions were also identified in a family with Tourette syndrome (PMID: 25129042), an individual with attention-deficit hyperactivity disorder (inherited; PMID: 19546859), and an individual with schizophrenia (inheritance unknown; PMID: 30208311). In addition, disruption of DPP6 has been reported in association with other phenotypes, including a chromosomal inversion disrupting DPP6 in a three-generation pedigree with autosomal dominant Alzheimer’s disease (PMID: 30874922), and a translocation disrupting DPP6 in an otherwise healthy male with azoospermia and in his mother and sister with normal phenotype (PMID: 24937803).

With respect to sequence variants, five nonsense variants, including one de novo and four without inheritance information, were identified in exome studies of autism spectrum disorder (PMIDs: 31452935, 31981491). Protein truncating variants have also been reported in an individual with schizophrenia (PMID: 27694994), two individuals with frontotemporal dementia (PMID: 30874922), and two parents of patients with autism (PMID: 31981491), but also in 50 subjects in gnomAD. Taken together, the available genetic evidence fails to support a role for heterozygous disruption of DPP6 in ID, autism or other neurodevelopmental disorders. DPP6 encodes an auxiliary subunit of Kv4.2 potassium channels. Dpp6 knockout mice exhibit impaired hippocampal synaptic development and function, learning and memory deficits, and reduced body and brain weight (PMIDs: 21943606, 23912628, 29651237). The effects of heterozygous loss of Dpp6 were not examined in these studies. Due to the limited human genetic evidence for DPP6, the experimental evidence was not scored. In summary, the gene-disease relationship between DPP6 and autosomal dominant complex neurodevelopmental disorder is disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 05/05/2021 (SOP Version 8).