Clinical and genetic characterization of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy caused by a plakophilin-2 splice mutation.

OBJECTIVES: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. METHODS: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. RESULTS: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. CONCLUSIONS: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.

Age of mother and grandmother in relation to a subject's breast cancer risk.

BACKGROUND: On theoretical grounds, the age of the grandmother and the age of the mother at delivery of her daughter may affect the breast cancer risk of the granddaughter. METHODS: We used the data relating to the Diagnostic Research Mamma-carcinoma cohort (DOM (Diagnostisch Onderzoek Mammacarcinoom) 3), which comprises a population-based sample of 12 178 women aged 41-63 years at enrolment in 1982-85 and followed up until 2000. During follow-up 340 postmenopausal breast cancer cases were identified. To these we applied a case-cohort design together with a random sample from the baseline cohort (n=1826). Of these study participants, we were able to retrieve the birth dates of 998 mothers (309 cases, 689 controls), and for 547 of these we also retrieved the birth dates of the grandmothers (197 cases, 350 controls). A weighted Cox proportional hazards model was used to estimate the hazard ratios (HRs) for the effect of the age of the grandmother and the age of the mother on the breast cancer risk of the index women, while adjusting for potential confounders. RESULTS: Compared with the reference group aged 25-29.9 years, the group with the lowest maternal age (<25 years) had an age-adjusted HR of 0.77 (95% CI 0.19-3.12) and the group with the highest maternal age (> or = 40 years) had an age-adjusted HR of 1.58 (95% CI 0.01-267.81), P-value for trend=0.62. Compared with the same reference group, the group with the lowest grandmaternal age (<25 years) had an age-adjusted HR of 0.53 (95% CI 0.24-1.17) and the group with the highest grandmaternal age (> or = 40 years) had an age-adjusted HR of 7.29 (95% CI 1.20-44.46), P for trend=0.04. The associations did not change significantly after additional adjustment for various risk factors for breast cancer, neither for maternal age nor for grandmaternal age. CONCLUSION: This study does not suggest a major role of maternal age at delivery or grandmaternal age at delivery of the mother for the (grand)daughters' breast cancer risk.

Heterogeneity in the origin of recurrent complete hydatidiform moles: not all women with multiple molar pregnancies have biparental moles.

Hydatidiform moles of two women, each with three molar pregnancies, were examined in order to study their origin. Multiple recurrences have previously been associated with women who have biparental complete hydatidiform moles (CHM). However, all the moles examined in this study were androgenetic CHM (AnCHM), indicating that recurrent (>2) moles, particularly in the absence of a positive family history, may be androgenetic rather than biparental. These data suggest that some women have a specific liability for having AnCHM. Making the distinction between a biparental or an androgenetic origin of recurrent moles is of relevance for counselling and when considering therapeutic options. Therefore, we propose that all recurrent moles should be investigated using molecular techniques.

Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder characterized by an aberrant vascular development. The resulting vascular lesions range from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations, especially in the skin, lung, gastrointestinal tract and the brain. Mutations in the genes encoding endoglin (ENG, chromosome 9q34) and activin A receptor type-like kinase 1 (ALK-1, also named ACVRL1, chromosome 12q13) are associated with HHT1 and HHT2, respectively. We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene. In most of the probands, we found a mutation in one of the two genes: 53% in the ENG gene and 40% in the ALK-1 gene. In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations.

Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population.

Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort (approximately 900 individuals) for SCA14 mutations in the Cys2 region of the PRKCG gene. We identified the Gly118Asp mutation in another eight individuals from five small families. Haplotype analysis identified a shared chromosomal region surrounding the SCA14 gene, and genealogical research was able to link all these ADCA patients to a single common ancestor. We therefore confirmed that the Gly118Asp mutation is a SCA14 founder mutation in the Dutch ADCA population.

Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family.

OBJECTIVE: To report a Dutch family with autosomal dominant cerebellar ataxia (ADCA) based on a novel mutation in the PRKCG gene. METHODS: The authors studied 13 affected members of the six-generation family. After excluding the known spinocerebellar ataxia (SCA) genes, a combination of the shared haplotype approach, linkage analysis, and genealogic investigations was used. Exons 4 and 5 of the candidate gene, PRKCG, were sequenced. RESULTS: Affected subjects displayed a relatively uncomplicated, slowly progressive cerebellar syndrome, with a mean age at onset of 40.8 years. A focal dystonia in two subjects with an onset of disease in their early 20s suggests extrapyramidal features in early onset disease. Significant linkage to a locus on chromosome 19q was found, overlapping the SCA-14 region. Based on the recent description of three missense mutations in the PRKCG gene, located within the boundaries of the SCA-14 locus, we sequenced exons 4 and 5 of this gene and detected a novel missense mutation in exon 4, which involves a G-->A transition in nucleotide 353 and results in a glycine-to-aspartic acid substitution at residue 118. CONCLUSION: A SCA-14-linked Dutch ADCA family with a novel missense mutation in the PRKCG gene was identified.