Loss of Function Variants in the XPC Causes Severe Xeroderma Pigmentosum in Three Large Consanguineous Families

Abstract

Background Xeroderma pigmentosum (XP) is a rare recessively inherited disorder that presents clinical and genetic heterogeneity. Mutations in eight genes, of which seven are involved in nucleotide excision repair (NER) pathway have been reported to cause the XP.

Methods and Results Three large consanguineous families of Pakistani origin displaying typical clinical hallmarks of XP were evaluated at clinical and molecular level. Homozygosity mapping using microsatellite markers established linkage of the families to XPC gene on chromosome 3p25.1. Sanger sequencing of the XPC gene identified a novel homozygous single bp deletion [NM_004628.5; c.1934del; p.(Pro645Leufs*5)] and two previously reported mutations that included a nonsense [c.1243 C>T; p.(Arg415*)] and a splice acceptor site (c.2251–1 G>C), all segregating with the disease phenotypes in the families.

Conclusion This report has extended the spectrum of mutations in the XPC gene and will also facilitate in diagnosis of XP and counselling of families inheriting it, which is the only inevitable tool for preventing the disease occurrence in future generations.

Zusammenfassung

Hintergrund Xeroderma pigmentosum (XP) ist eine seltene, rezessive Erbkrankheit, die sich durch Heterogenität des klini-schen Erscheinungsbilds und der zugrunde liegenden genetischen Veränderungen auszeichnet. Mutationen in acht Genen, von denen sieben an der Nukleotidexzisionsreparatur (NER) beteiligt sind, wurden als ursächlich für die Entstehung von XP beschrieben.

Methodik und Ergebnisse Drei große konsanguine Familien pakistanischer Herkunft, welche die für XP charakteristischen klinische Merkmalen aufweisen, wurden auf klinischer und molekularer Ebene untersucht. Durch Homozygotie-Kartierung mittels Mikrosatelliten-Markern konnte eine Verbindung der Familien zum XPC-Gen auf Chromosom 3p25.1 nachgewiesen werden. Die Sanger-Sequenzierung des XPC-Gens fand eine neue homozygote einzelne bp-Deletion [NM_004628.5; c.1934del; p.(Pro645Leufs * 5)] und zwei zuvor bereits berichtete Mutationen, darunter eine Non-sense- [c.1243 C > T; p.(Arg415 *)] und eine Spleißakzeptorstelle (c.2251–1 G > C), die alle mit Krankheitsphänotypen-Segregation in den Familien einhergingen.

Schlussfolgerung Der vorliegende Bericht erweitert das Spektrum der Mutationen im XPC-Gen und erleichtert auch die Diagnostik von XP und die Beratung der betroffenen Familien, die als einziges Instrument das Auftreten der Krankheit in künftigen Generationen verhindern kann.

Key words

Xeroderma pigmentosum - Pakistani families - Homozygosity mapping - XPC gene - Novel frameshift mutation

Schlüsselwörter

Xeroderma pigmentosum - pakistanische Familien - Homozygotie-Kartierung - XPC-Gen - neue Frameshift-Mutation

Publikationsverlauf

Artikel online veröffentlicht:
20. September 2021

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