AFF3 – KINSSHIP syndrome

The transcriptional activator AFF3 (AFF3) is definitively associated with KINSSHIP syndrome (KINSSHIP syndrome), an autosomal dominant disorder characterized by intellectual disability, mesomelic dysplasia, horseshoe kidney, seizures, hypertrichosis, and pulmonary involvement. Initial reports described de novo missense variants in the nine–amino‐acid degron of AFF3 in 16 unrelated probands plus two previously published cases (n=18 probands) (PMID:33961779).

Subsequent studies identified three patients with mosaic and germline degron variants in AFF3, expanding the phenotypic spectrum and confirming pathogenicity across unrelated families (PMID:36576140). A recent cohort screen uncovered one individual with a de novo partial AFF3 duplication and 17 individuals harboring heterozygous loss-of-function or biallelic missense variants, consistent with a semi-dominant effect (n=18 additional) (PMID:38811945).

The inheritance mode is autosomal dominant with de novo occurrence; mosaicism has been documented but no multi-generation segregation beyond parental mosaic carriers has been reported. No unaffected individuals carrying truncating or degron variants have been documented in deep population databases, supporting high penetrance.

Functional studies demonstrate a dominant-negative mode of action and dosage sensitivity. Knockin mouse models and overexpression of mutant AFF3 in zebrafish recapitulate key features of KINSSHIP syndrome. Zebrafish knockdown phenotypes are rescued by wild-type AFF3 mRNA, whereas overexpression of mutated AFF3 transcripts increases abnormal larvae (PMID:33961779; PMID:38811945).

In vitro transcriptome profiling of isogenic human cell lines with homozygous degron (DN/DN) or loss-of-function (LoF/LoF) genotypes shows differential modulation of more than one-third of AFF3-bound loci. Although the same pathways (e.g., DNA repair) are affected, only one-third of differentially expressed genes overlap, indicating distinct molecular consequences of DN versus LoF variants (PMID:38293053).

Collectively, over 36 unrelated probands with consistent clinical features, robust animal and cellular model concordance, and absence of conflicting data support a Definitive gene–disease association. Key take-home: AFF3 variant screening is critical for diagnosis of KINSSHIP syndrome and informs patient management and genetic counseling.

References

• American journal of human genetics | 2021 | Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. PMID:33961779
• Clinical genetics | 2023 | Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants. PMID:36576140
• Genome medicine | 2024 | Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles. PMID:38811945
• medRxiv | 2024 | Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles. PMID:38293053

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