Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark.

Palmoplantar keratoderma (PPK) is a heterogeneous group of rare skin diseases characterized by hyperkeratosis on the palms or soles. The subtype isolated punctate PPK is caused by heterozygous variants in AAGAB. We investigated if the variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate PPK in the Region of Southern Denmark represented a founder variant and estimated the age to the most recent common ancestor. We performed haplotype analysis on samples from 20 patients diagnosed with punctate PPK and the AAGAB c.370C>T, p.Arg124Ter variant. Using the Gamma Method, we calculated the years to the most recent common ancestor. We also explored the presence of the variant in other populations through literature and databases (HGMD, ClinVar, and gnomAD). Our analysis revealed a shared haplotype of 3.0 Mb, suggesting shared ancestry. The ancestral haplogroup was estimated to an age of 12.1 generations (CI: 4.9-20.3) equivalent to approximately 339 years (CI: 137-568). This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant. We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK.

Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: when genetic diagnosis influences choice of treatment strategy.

Pityriasis rubra pilaris (PRP) is a rare dermatosis characterised by hyperkeratotic follicular papules, orange-red scaly plaques and palmoplantar keratoderma. The aetiology of the disease is in most cases unclear and treatment can be challenging. Familial cases of PRP may result from pathogenic variants in the caspase recruitment domain family member 14 (CARD14). We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14. Therapy with ustekinumab was initiated with remarkable effect, which improved the patient's quality of life significantly.