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Analysis of the haemophilia A mutation in sporadic patients registered at the Royal London Hospital and their families
Author(s) -
TAGLIAVACCA L.,
ROWLEY G.,
GREEN P. M.,
HAYDEN S.,
WOOSEY C.,
COLVIN B.,
GIANNELLI F.
Publication year - 1997
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1046/j.1365-2516.1997.00089.x
Subject(s) - medicine , grandparent , haemophilia , mutation , haemophilia a , germline mosaicism , aunt , genetics , pediatrics , germline , biology , gene , psychology , developmental psychology , sociology , anthropology
Summary . The families of sporadic haemophilia A patients registered at the Royal London Hospital and with living grandparents were selected for study. Twelve of the 13 known families agreed to collaborate. Of these 11 had a patient with severe and one a patient with mild haemophilia. Five of the severely affected patients had inversions of type 1, that is involving int22h‐1 and int22h‐3 , and two had inversions of type 2, that is involving int22h‐1 and int22h‐2 . The remaining four patients with severe disease had single base substitutions causing two different non‐sense (Gln592→Stop; Trp2313→Stop) and two different mis‐sense mutations (His267→Pro; Arg2209→Gln). A single base substitution causing a mis‐sense mutation (His1961→Asp) was also found in the patient with mild haemophilia. The Arg2209→Gln mutation has previously been found in other patients while the other single base substitutions have not hitherto been observed. Three mutations (all single base substitutions) appear to have arisen in the germline of the patient’s mother, while seven mutations originated in the gonad of one of the patient’s grandparents. In two of the latter families (both with inversion type 2) the origin of muta‐tions could be clearly assigned to the grandpaternal gonad. Data on parental age at the onset of mutation were ob‐tained in the families investigated. In addition, further evidence was obtained that the int‐22h‐related inversions arise by intrachromatid, intrachromosome homologous re‐combination as the int22h repeat sequences of a patient were found to be identical to those of the maternal grand‐father whose germline represents the origin of mutation.