Journal of Medical Genetics

Liou, C-W; Lin, T-K; Chen, J-B; Tiao, M-M; Weng, S-W; Chen, S-D; Chuang, Y-C; Chuang, J-H; Wang, P-W

doi: 10.1136/jmg.2010.077552pmid: 20837494

BackgroundA T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 16189 can generate a variable length polycytosine tract (poly-C). This tract variance has been associated with disease. A suggested pathogenesis is that it interferes with the replication process of mtDNA, which in turn decreases the mtDNA copy number and generates disease.MethodsIn this study, 837 healthy adults' blood samples were collected and determined for their mtDNA D-loop sequence. The mtDNA copy number in the leucocytes and serum levels of oxidative thiobarbituric acid reactive substance (TBARS) and antioxidative thiols were measured. All subjects were then categorised into three groups: wild type or variant mtDNA with presence of an interrupted/uninterrupted poly-C at 16180–16195 segment.ResultsA step-wise multiple linear regression analysis identified factors affecting expression of mtDNA copy number including TBARS, thiols, age, body mass index and the mtDNA poly-C variant. Subjects harbouring a variant uninterrupted poly-C showed lowest mean (SD) mtDNA copy number (330 (178)), whereas an increased copy number was noted in subjects harbouring variant, interrupted poly-C (420 (273)) in comparison with wild type (358 (215)). The difference between the three groups and between the uninterrupted poly-C and the composite data from the interrupted poly-C and wild type remained consistent after adjustment for TBARS, thiols, age and body mass index (p=0.001 and p=0.011, respectively). A trend for decreased mtDNA copy number in association with increased number of continuous cytosine within the 16180–16195 segment was noted (ptrend<0.006).ConclusionsOur results substantiate a previous suggestion that the mtDNA 16189 variant can cause alteration of mtDNA copy number in human blood cells.

Dupré, T; Vuillaumier-Barrot, S; Chantret, I; Yayé, H S; Le Bizec, C; Afenjar, A; Altuzarra, C; Barnérias, C; Burglen, L; de Lonlay, P; Feillet, F; Napuri, S; Seta, N; Moore, S E H

Christensen, A H; Benn, M; Bundgaard, H; Tybjærg-Hansen, A; Haunso, S; Svendsen, J H

doi: 10.1136/jmg.2010.077891pmid: 20864495

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins.ObjectiveTo thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status.Methods65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification.ResultsThe screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p.G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome.Conclusions33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.

Tsumagari, K; Chen, D; Hackman, J R; Bossler, A D; Ehrlich, M

doi: 10.1136/jmg.2009.076703pmid: 20710047

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4.MethodsWe developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles.ResultsAll (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10−4), and 26% had homozygous 4qB163 alleles.ConclusionsOur results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay.

Bellanné-Chantelot, C; Saint-Martin, C; Ribeiro, M-J; Vaury, C; Verkarre, V; Arnoux, J-B; Valayannopoulos, V; Gobrecht, S; Sempoux, C; Rahier, J; Fournet, J-C; Jaubert, F; Aigrain, Y; Nihoul-Fékété, C; de Lonlay, P

Wakeling, E L; Amero, S Abu; Alders, M; Bliek, J; Forsythe, E; Kumar, S; Lim, D H; MacDonald, F; Mackay, D J; Maher, E R; Moore, G E; Poole, R L; Price, S M; Tangeraas, T; Turner, C L S; Van Haelst, M M; Willoughby, C; Temple, I K; Cobben, J M

doi:

doi: 10.1136/jmg.2009.078964corr1pmid: N/A

doi: 10.1136/jmg.2009.073098corr1pmid: N/A

Halsall, Sally; Nicholas, Adeline K; Thornton, Gemma; Martin, Howard; Geoffrey Woods, C

doi: 10.1136/jmg.2010.079277pmid: 20679666

The authors report the unexpected finding of three different nonsense mutations in two unrelated individuals with a diagnosis of autosomal recessive primary microcephaly. In each case one phenotypically normal parent was found to carry two of the nonsense mutations, presumably in cis. This finding of ‘triple pathogenic mutations’ is of unknown incidence but has significant implication for genetic counselling. A failure to detect all three mutations could result in both false positive and false negative diagnoses in other family members. Both of these potential problems can be avoided by always genotyping the parents.

Wilson, J R F; Bateman, A C; Hanson, H; An, Q; Evans, G; Rahman, N; Jones, J L; Eccles, D M

doi: 10.1136/jmg.2010.078113pmid: 20805372

IntroductionThe Li–Fraumeni Syndrome is caused by a germline TP53 mutation and is associated with a high risk of breast cancer at young ages. Basal (triple negative) breast cancers are now well recognised to be a typical sub-type of breast cancer developing in a large proportion of BRCA1 gene carriers. We considered whether a similar narrow sub-type of breast cancer was found in TP53 gene mutation carriers.ObjectiveA hypothesis generating study to investigate whether there are specific breast tumour characteristics associated with germline TP53 mutations.MethodsPathological characteristics in 12 breast cancers arising in nine patients carrying pathogenic TP53 mutations were compared to a reference panel of 231 young onset breast tumours included in the POSH study.ResultsPatients carrying a TP53 mutation showed a significantly higher likelihood of developing a breast cancer with Human Epidermal growth factor Receptor (HER2) amplification (83%) when compared to the cohort of young onset breast cancer cases (16%); ER and PR status were equivalent between groups.ConclusionThese findings suggest that breast cancer developing on a background of an inherited TP53 mutation is highly likely to present with amplification of HER2.