Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.

OBJECTIVE: To determine the prevalence of desmosomal gene mutations in athletes with complex arrhythmias (VA) of right ventricular (RV) origin and structural RV abnormalities to evaluate whether there is sufficient genetic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC) to consider them the same or different entities. DESIGN: Observational cohort SETTING: Tertiary hospital referrals PATIENTS: Forty-seven consecutive athletes (age 42 (11) years) with complex VA of RV morphology (excluding idiopathic right ventricular outflow tract ventricular tachycardia), who performed 14 (9) h/week of moderate to intense sport practise for 19 (9) years. INTERVENTIONS: Clinical evaluation (detailed sports history, multi-modality imaging, electrophysiological study) and sequencing of five candidate desmosomal genes. RESULTS: A clinical diagnosis of definite or suspected ARVC by task force criteria (TFC) was met in 24 (51%) and 17 (36%), respectively. ARVC classification was not related to the rate of major arrhythmic events (p=0.28). Pathogenic mutations (four novel) were identified in six athletes (12.8%), which is below published rates for familial ARVC (27-52%). Moreover, only two athletes had a suggestive family history. Severe RV dysfunction was more frequent in mutation carriers (33% vs 2%, p=0.04), but otherwise TFC features were similar to those without mutations. No mutations were found in the 20 athletes performing more than average weekly exercise, yet all met the criteria for definite or suspected ARVC. CONCLUSIONS: In this athletic cohort, we found lower than expected rates of desmosomal gene mutations, particularly among those performing the most exercise. This adds further weight to the hypothesis that an ARVC-like phenotype may be acquired through intense exercise without an identifiable genetic predisposition.

Complex chromosome re-arrangement 45,X,t(Y;9) in a girl with sex reversal and mental retardation.

A girl with mental retardation and multiple minor anomalies was found to have a complex chromosome 9p re-arrangement comprising a deleted, translocated Y chromosome, a deletion of the sex reversal gene region (DMRT1) at 9p, together with an inverted duplication of the more proximal part of 9p. The karyotype was 45,X,der(Y;9)(Ypter-->Yq12::9p21.1-->9p22.2::9p22.2-->9qter) de novo. The karyotypic male, phenotypic female had a dysgerminoma of the left dysplastic ovary. The patient had typical 'trisomy 9p' syndrome, and we propose that the critical region for this phenotype is located between 9p22.1 and 9p22.2.

Apparently new autosomal dominant Spondyloepimetaphyseal dysplasia: gonadal mosaicism onset.

We report a family in which an apparently previously undescribed form of Spondyloepimetaphyseal dysplasia (SEMD) presented after probable gonadal mosaicism occurred and is inherited in an autosomal dominant mode. The other autosomal dominant SEMDs are compared.

Familial adenomatous polyposis in two Black South African families.

The apparent low incidence of colon cancer in the Black population of South Africa has been ascribed to a non-Western diet. The present authors report the identification of two common 5-bp deletions at codons 1309 and 1061 of the adenomatous polyposis coli (APC) gene in a Xhosa and Zulu patient, respectively. The in vitro transcription/translation test (PTT) and a non-radioactive heteroduplex method, which facilitates resolution of enzymatically amplified DNA by agarose gel electrophoresis, were used for mutation detection. This study represents the first report of APC mutations in indigenous Black individuals clinically diagnosed with familial adenomatous polyposis coli (FAP). The two deletion mutations are responsible for FAP in 35% of affected South Africans, a frequency similar to that described in several other non-African populations. The apparently low incidence of colon cancer in the African population may be ascribed either to the rare occurrence of the 'second hit' needed for polyp formation or to a lower incidence of mutations in the APC gene.

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.

Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070)

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

Lethal neonatal mandibuloacral dysplasia.

We report on a case of lethal neonatal mandibuloacral dysplasia. Large confluent fontanelles, sparse fine hair and eyebrows, pseudo-exophthalmos, micrognathia, bulbar digits, and short clavicles were present. In addition, we describe for the first time the presence of glandular hypospadias in this disorder. We propose that this neonatally lethal case represents severe expression of mandibuloacral dysplasia.

First report of CFTR mutations in black cystic fibrosis patients of southern African origin.

Cystic fibrosis (CF) is thought to be rare in the black populations of Africa who have minimal white admixture. Only a few cases have been reported but have not been studied at the molecular level. We report the detection of CFTR mutations in three southern African black patients. One was homozygous for the 3120 + 1G-->A mutation, while the other two were compound heterozygotes each with this mutation on one chromosome. The other mutations were G1249E and a previously unreported in frame 54 bp deletion within exon 17a involving nucleotides 3196-3249 (3196del54). The 3120 + 1G-->A mutation was first described in American black patients and has been shown to be a common mutation in this population (9-14% of CF chromosomes). It was also found in a black CF patient whose father, the 3120 + 1G-->A carrier, is from Cameroon. These data suggest that it is an old mutation which accounts for many of the CFTR mutations in African blacks.

Maternal origin of extra haploid set of chromosomes in third trimester triploid fetuses.

Twenty-six highly polymorphic markers were used to determine the origin of the extra haploid chromosome set in 6 triploid fetuses of type II phenotype. All had reached the third trimester of pregnancy. The extra set was maternal in origin in all cases, supporting previous research indicating longer in utero survival of maternally-derived triploid fetuses. These findings provide evidence for an instance of genomic imprinting in humans.

Genetic mapping of the FACC gene and linkage analysis in Fanconi anaemia families.

Fanconi anaemia is an autosomal recessive disorder associated with increased chromosome breakage and progressive bone marrow failure. The gene for complementation group C (FACC) has been cloned and mapped to chromosome 9q22.3, but neither its genetic location nor the proportion of patients belonging to group C is known. We have used a polymorphism within the FACC gene to localise it within a 5 cM interval on chromosome 9q, bounded by D9S196/D9S197 and D9S176. The genes for Gorlin's syndrome and multiple self-healing squamous epitheliomata have also been mapped to this interval. Linkage analysis with the three highly informative microsatellite polymorphisms flanking FACC in 36 Fanconi anaemia families showed that only 8% of families were linked to this locus. This indicates that the genes for the other Fanconi anaemia complementation groups must map to one or more different chromosomal locations. The markers also allowed rapid exclusion of 56% of the families in our panel from complementation group C, thus substantially reducing the number of patients who need to be screened for FACC mutations.

Bandwidths of respiratory gas flow and pressure waveforms in mechanically ventilated infants.

The frequency content of airway pressure and gas flow in mechanically ventilated infants (MVIS) has not been adequately investigated. Pressure-cycled infant ventilators generate pressure pulses with short rise-times. Gas flow is approximately equal to the derivative of pressure when lung compliance is low, and hence contains high-frequency components. We defined bandwidth as that frequency fm below which 99.9% of the energy of the signal resided. Simulation of the measurement process using measurement systems with frequency response similar to sixth-order Bessel filters and a lung model comprising series resistance, inertance and compliance showed that measurement systems with frequency response flat +/- 10% to fm yield time domain errors less than 3% of the peak value. We digitized pressure and flow signals from 10-20 ventilator (Healthdyne 105) breaths in 33 stable MVIS. The transducers' (Gould P50, Hans Rudolph 8300 screen pneumotach) frequency responses had been measured between 1 Hz and 100 Hz and phase matched at 10 Hz. We calculated total respiratory resistance R and elastance E using multiple linear regression, and ensemble-average power spectral density using the FFT with a rectangular time window and padding to 2048 points. Power spectra were compensated for non-unity transducer and anti-alias filter responses up to 60 Hz. Measured data sequences that were not self-windowing due to spontaneous breathing efforts, that yielded regression R2 < 0.95 or that contained flow oscillations due to secretions in the airway were discarded. Satisfactory results were obtained from more than eight breaths in 18 infants. Mean bandwidths (+/- SD) of pressure and flow waveforms were 4.7 +/- 0.7, range 3.5-5.9 and 19.6 +/- 6.5, range 10.8-32.1 Hz, respectively. Flow bandwidths B correlated with the respiratory time constant tau (B = -77.2 tau + 26.8, R2 = 0.55, P < 0.0002), and with elastance E (B = 61.4E + 10.1, R2 = 0.74, P < 0.0001). We conclude that the bandwidth of the flow waveform increases with decreasing compliance and mechanical time constant. The frequency response of pressure and flow measurement systems should be flat +/- 10% at least up to 6 and 32 Hz respectively to obtain data with dynamic errors less than 3% in infants with low-compliance lung disease.