Submission Details

KPTN encodes a component of the mTOR regulatory complex KICSTOR. KPTN was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2014 (Baple et al., PMID: 24239382). The disorder is characterized by global developmental delay, intellectual disability, hypotonia, macrocephaly with frontal bossing, and facial dysmorphic features. Additionally, more variable features can include seizures, anxiety, and autistic features.

Six variants (2 frameshift, 2 splice, 1 nonsense, and 1 inframe insertion) that have been reported in 9 probands in 6 publications (PMIDs: 24239382, 25847626, 31999056, 32358097, 32808430, 36703628) are included in this curation. Variants in this gene segregated with disease in 11 additional family members. Nine affected individuals belong to 4 nuclear families from a single extended Amish pedigree; all are homozygous or compound heterozygous for two founder variants (p.Ser259* and p.Met241_Gln246dup) (PMID: 24239382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function.

This gene-disease relationship is also supported by functional alterations in non-patient cells, and a Kptn null mouse model that exhibits cognitive deficits, macrocephaly, and increased mTOR signalling (PMID: 37437211).

In summary, there is definitive evidence supporting the relationship between KPTN and autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2025 (SOP Version 11).

KPTN encodes a component of the mTOR regulatory complex KICSTOR. KPTN was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2014 (Baple et al., PMID: 24239382). The disorder is characterized by global developmental delay, intellectual disability, hypotonia, macrocephaly with frontal bossing, and facial dysmorphic features. Additional, more variable features can include seizures, anxiety, and autistic features.

Six variants (2 frameshift, 2 splice, 1 nonsense, and 1 inframe insertion) that have been reported in 9 probands in 6 publications (PMIDs: 24239382, 25847626, 31999056, 32358097, 32808430, 36703628) are included in this curation. Variants in this gene segregated with disease in 11 additional family members. Nine affected individuals belong to 4 nuclear families from a single extended Amish pedigree; all are homozygous or compound heterozygous for two founder variants (p.Ser259* and p.Met241_Gln246dup) (PMID: 24239382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function.

This gene-disease relationship is also supported by functional alterations in non-patient cells, and a Kptn null mouse model that exhibits cognitive deficits, macrocephaly, and increased mTOR signalling (PMID: 37437211).

In summary, there is definitive evidence supporting the relationship between KPTN and autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2025 (SOP Version 11).