KANSL1 – Koolen-de Vries Syndrome

KANSL1 haploinsufficiency caused by 17q21.31 microdeletions or intragenic truncating variants is the established genetic basis of Koolen-de Vries syndrome (KdVS), an autosomal dominant neurodevelopmental disorder (PMID:22544363). Patients typically present with neonatal hypotonia (HP:0001252), global developmental delay (HP:0001263), moderate intellectual disability (HP:0001249), seizures (HP:0001250), and characteristic facial dysmorphism (HP:0001999).

Genetic findings include de novo frameshift and splice-site variants as well as microdeletions encompassing KANSL1. To date, >45 individuals with SNVs or small indels and >33 with 17q21.31 microdeletions have been reported affecting KANSL1, including c.808_809del (p.Leu270fs) (PMID:26306646). The variant spectrum comprises missense, nonsense, splice, frameshift, and structural deletions (PMID:26306646; PMID:36104871). Most deleterious alleles arise de novo without familial recurrence.

Segregation analysis is limited by predominant de novo occurrence, with no unaffected carriers reported among relatives. Microdeletion cohorts and SNV cases demonstrate full penetrance for core neurodevelopmental features and facial gestalt, irrespective of variant type.

Functional studies support haploinsufficiency as the pathogenic mechanism. KANSL1 regulates histone H4 lysine 16 acetylation via the NSL complex, and patient-derived cell lines show reduced H4K16ac (PMID:22544363). Drosophila mutants display learning deficits, while Kansl1+/- and 17q21.31 deletion mice recapitulate cognitive impairment, craniofacial anomalies, and synaptic transmission defects (PMID:28704368). A robust blood DNA methylation episignature further discriminates KdVS individuals and aids variant classification (PMID:38282074).

The phenotypic spectrum extends from severe cognitive impairment to mild speech-predominant delay, variable epilepsy with potential resolution by adolescence, ocular anomalies, and stable musculoskeletal features in adulthood (PMID:26306646; PMID:33361104). Episignature and next-generation phenotyping enhance diagnostic accuracy, particularly for small deletions and VUS.

Conflicting data include misassigned benign variants such as c.985_986del (p.Leu329fs) due to mapping artifacts and a lack of association of common KANSL1 alleles in self-limited focal epilepsy cohorts (PMID:33050294; PMID:29352316). These underscore the necessity for careful molecular and clinical correlation.

Overall, the wealth of de novo truncating variants, consistent functional model data, and corroborative multi-omic signatures over >10 years establish a Definitive gene–disease relationship. This knowledge underpins targeted genetic testing, informs prognostic counseling, and guides potential therapeutic explorations.

References

• Nature Genetics • 2012 • Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. PMID:22544363
• European Journal of Human Genetics • 2016 • The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. PMID:26306646
• American Journal of Medical Genetics Part A • 2017 • 10-year-old female with intragenic KANSL1 mutation, no KANSL1-related intellectual disability, and preserved verbal intelligence. PMID:28211987
• Human Mutation • 2022 • Next-generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen-de Vries syndrome. PMID:36104871
• PLoS Genetics • 2017 • Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition. PMID:28704368
• Genes • 2020 • Clinical Genetics Can Solve the Pitfalls of Genome-Wide Investigations: Lesson from Mismapping a Loss-of-Function Variant in KANSL1. PMID:33050294
• European Journal of Human Genetics • 2024 • A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells. PMID:38282074

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