Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis

Abstract

A predominance of de novo mutations in the paternal germ line has been reported for several disorders; however, in familial adenomatous polyposis (FAP), the parental origin of APC mutations has been scarcely analysed so far. Among 563 unrelated FAP families with known family history, we identified 58 patients with a suspected de novo mutation in the APC gene. A germline mutation was detected in 52 of them; in 38 patients, the mutation could be excluded in both parents. The five base pair deletion at codon 1309 (c.3927_3931delAAAGA) was over-represented in the group of patients with suspected de novo mutations (17/58 ¼ 29%), when compared to the group of familial cases (26/505 ¼ 5%); thus, the high frequency of this mutation is not due to a founder effect but rather due to de novo mutation events. Parental origin of de novo mutations could be traced in 16 families, including three families with large chromosomal deletions. Four mutations were of maternal and 12 of paternal origin, pointing to a moderate preponderance towards paternal origin. Sex-related differences of mutation types could be observed: large deletions and single-base substitutions were exclusively of paternal origin, whereas the small deletions were equally distributed (maternal/paternal ratio 4:4).

Sequencing of isolated sperm cells for direct haplotyping of a human genome

“…Knowledge of haplotype structure is critical for understanding allele-specific events, such as methylation, that are cis-regulated (Tycko 2010), and it can provide valuable validation data for the study of population genetics (Conrad et al 2006) and genetic ancestry (Green et al 2010). The haplotype structure of an individual's genome is also essential for predicting instances of compound heterozygosity (McLaughlin et al 2010;Ng et al 2010) or for identifying the parental origins of de novo mutations (Glaser et al 2000;Aretz et al 2004).…”

From Gardner fibroma diagnosis to constitutional APC mutation detection: a one‐way street

“…Recent studies indicated the presence of mosaicism in approximately 15% of parents of apparently sporadic cases 7, 8.…”

Clinical Utility Gene Card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) - update 2014

“…1, 2 • De novo events: 10-40%. 1, 3,4 • Broad spectrum of point mutations, 490% are truncating (nonsense, del/ins, splice sites). 2 • Mutational hot spots: c.3927_3931delAAAGA;p.(Glu1309Aspfs*4) (11%), c.3183_3187delACAAA; p.(Gln1062*) (7%), c.637C4T;p. (Arg213*) (3%), c.3202_3205delTCAA;p.(Ser1068Glyfs*57) (2%).…”