ANKRD17 – Chopra-Amiel-Gordon syndrome

Chopra-Amiel-Gordon syndrome is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, intellectual disability, speech and language impairment, seizures, and recurrent infections. It arises from heterozygous loss-of-function variants in ANKRD17, encoding an ankyrin repeat–containing protein essential for cell cycle progression.

A cohort of 34 individuals from 32 families exhibited de novo ANKRD17 variants, including 21 truncating or essential splice-site variants, 9 missense variants, 1 in-frame insertion–deletion, and 1 microdeletion (PMID:33909992). These 32 unique variant alleles support a loss-of-function mechanism consistent with haploinsufficiency.

In addition, a 4-year-old female patient with core phenotypes harboring a novel heterozygous missense variant c.7778A>C (p.His2593Pro) was reported, expanding the mutational spectrum (PMID:37456926).

A splicing variant c.7248+1G>A causing exon 32 skipping and premature termination (p.Asp2357fs) was identified in a Chinese juvenile with developmental delay and transient tic disorder, validated by RNA analysis (PMID:39315309).

Functional assays and protein modeling in Drosophila implicate ANKRD17 in Hippo pathway regulation, and structural analyses predict that missense variants destabilize ankyrin repeats. Single-cell RNA-seq data demonstrate ANKRD17 expression across neurogenesis in the developing human telencephalon, corroborating its role in brain development (PMID:33909992).

No conflicting evidence has been reported. Testing for heterozygous ANKRD17 variants is recommended in individuals with suggestive neurodevelopmental phenotypes. Key take-home: ANKRD17 haploinsufficiency underlies Chopra-Amiel-Gordon syndrome, informing diagnosis and genetic counseling.

References

• American journal of human genetics • 2021 • Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism. PMID:33909992
• SAGE open medical case reports • 2023 • A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report. PMID:37456926
• Frontiers in genetics • 2024 • Case report: Whole exome sequencing reveals a novel splicing variant of ANKRD17 gene in a Chinese male juvenile with developmental delay and transient tic disorder. PMID:39315309

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