Large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies

Summary

Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131–6delins - TCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation.

Conclusions

Large deletions play a minor but essential role in the mutational spectrum of the F7 and F10 genes. Copy number analyses (e. g. MLPA) should be considered if sequencing cannot clarify the underlying reason of an observed coagulopathy. Of note, in cases of combined FVII/FX deficiency, a deletion of the two contiguous genes might be part of a larger chromosomal rearrangement.

Zusammenfassung

Der angeborene Faktor-VII-Mangel gehört wie der Faktor-X-Mangel zu den seltenen Gerinnungsstörungen. Sie können isoliert oder kombiniert vorkommen, weil die F7- und F10-Gene auf Chromosom 13 gekoppelt vorliegen. Wir berichten über die molekulargenetische Diagnostik von 192 Index-Patienten mit FVIIund/ oder FX-Mangel. 10 neue und 53 bekannte Veränderungen im F7-Gen sowie 5 neue und 11 bekannte Sequenzveränderungen im F10-Gen konnten identifiziert werden, darunter eine homozygote 4.35 kb große Deletion innerhalb des F7-Gens (c.64+430_131–6delinsTCGTAA) und drei heterozygote Deletionen der F7- und F10-Gene. Eine von diesen fand sich bei einer entwicklungsverzögerten Patientin mit Agenesie des Corpus callosum und war in der konventionellen Chromosomenanalyse sichtbar als 13q34-Deletion.

Schlussfolgerungen

Große F7- und F10-Gendeletionen spielen folglich im Einzelfall eine wichtige Rolle. Kopienzahlanalysen (z. B. MLPA) sind sinnvoll, wenn durch die Sequenzierung keine Erklärung für den beobachteten FVII- und/oder FX-Mangel gefunden wird. Auch kann der Nachweis einer Deletion der beiden benachbarten F7-und F10-Gene bei einem kombinierten Mangel ein Hinweis auf ein größeres chromosomales Rearrangement sein.

Keywords

Factor VII deficiency - factor X deficiency - F7 gene - F10 gene - chromosome 13q34 deletion

Schlüsselwörter

FVII-Mangel - FX-Mangel - F7-Gen - F10-Gen - Chromosom-13q34-Deletion

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