A KIAA0586 c.1815G>A Founder Allele Associated with Short-Rib Polydactyly Syndrome Type IV in Romani Families
Kellermayer, R.; Farooq, M.; Bene, J.; Elcioglu, N.; Harris, R. A.; Szigeti, R. G.; Teszas, A.; Tommerup, N.; Larsen, L. A.; Melegh, B.; Hadzsiev, K.
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Background: Short-rib polydactyly syndrome type IV (Beemer-Langer syndrome) is a lethal skeletal ciliopathy that can result from biallelic pathogenic variants in KIAA0586 (TALPID3). Earlier clinical observations suggested an unusually high occurrence of this phenotype in Romani families from the Carpathian Basin. Methods: Whole-exome sequencing was performed in affected individuals from five independent families, and the frequency of KIAA0586 c.1815G>A was assessed in a Hungarian Romani genetic database of 500 individuals. Results: The affected individuals were homozygous for c.1815G>A, a splice-disrupting variant previously shown to cause exon 14 skipping. Four families self-identified as Roma from Hungary and one affected individual was from Turkey. Six heterozygous carriers were identified among 500 individuals in the Hungarian Romani cohort, corresponding to an allele frequency of 0.6%. This was markedly higher than the frequencies cited from ALFA (0.01%) and gnomAD (0.0014%). The Hungarian-Romani and Turkish affected individuals also shared genotypes at informative markers flanking the variant, supporting a shared ancestral haplotype. Conclusions: These observations strengthen evidence that KIAA0586 c.1815G>A is a founder allele enriched in at least some Romani populations. The data support consideration of ancestry-informed carrier testing in appropriately counseled families. Historical admixture may explain the occurrence of the same haplotype in a Turkish case, but this remains a hypothesis requiring broader population-genomic confirmation.
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