84 research outputs found
Genetic determination of the left-right axis in man: A homozygosity mapping study of heterotaxia in an inbred population
No full textAll vertebrate species show bilateral asymmetry about the midline. Orientation of the heart and viscera is nonrandom or handed and this handed asymmetry is conserved between species. Defects of lateralization include complete situs inversus and heterotaxia in which individual organ situs is discordant. Heterotaxia is almost always associated with complex heart defects. In man the aetiology of most defects of lateralization is unknown but familial cases provide evidence for a genetic component. Study of animal models shows that determination of left right asymmetry is a complex process under the control of many different genes. A series of 68 patients with laterality disturbance ascertained through Paediatric Cardiology Centres is described. The majority of patients had right or left isomerism sequence. There were 43 sporadic cases, 12 familial cases and 13 cases with consanguineous parents. In an attempt to localise a gene for heterotaxia, a homozygosity mapping study was undertaken using 11 patients of Pakistani origin and their consanguineous parents. A whole genome screen with average marker spacing of 14cM was performed. No regions were found to be homozygous by descent (HBD) in all 11 probands. All potential regions of shared HBD in 6 or more affected individuals were excluded by genotyping intervening markers. It is likely that this approach was unsuccessful because heterotaxia is genetically heterogeneous even within this genetically isolated population. Further linkage studies should be confined to single inbred pedigrees. Mutations in the gene for the gap junction protein , connexin 43, have been reported in patients with isomerism sequence. Direct sequencing of the carboxy terminal of connexin 43 in 50 patients did not reveal any changes from the published consensus sequence. The role of this gene in establishing left right asymmetry remains to be proved
Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1
No full textThe imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith–Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.<br/
SET de novo frameshift variants associated with developmental delay and intellectual disabilities
No full text
Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications
No full textAutozygosity Mapping of a Seckel Syndrome Locus to Chromosome 3q22.1-q24
No full textSeckel syndrome (MIM 210600) is an autosomal recessive disorder of low birth weight, severe microcephaly, and dysmorphic facial appearance with receding forehead, prominent nose, and micrognathia. We have performed a genomic screen in two consanguineous families of Pakistani origin and found that the disorder segregates with markers between loci D3S1316 and D3S3710, which map to chromosome 3q22.1-q24. Analysis using HOMOZ/MAPMAKER gave a maximum LOD score of 8.72. All five affected individuals were homozygous for the same allele, for two adjacent polymorphic markers within the region segregating with the disease, narrowing the region to 12 cM
Patterns of recurrence of congenital heart disease An analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography
No full textAbstractObjectivesWe sought to investigate the pattern of recurrence of congenital heart disease (CHD) where there is one or more affected first-degree relative.BackgroundThere are little data on patterns of recurrence of different types of CHD. Analysis of a fetal series allows a high ascertainment of affected cases.MethodsWe performed an analysis of referrals for detailed fetal echocardiography to a tertiary fetal cardiology unit, where there was a first-degree family history of CHD from 1990 to the end of 1999. Data were entered prospectively on a computerized database. Recurrences were exactly concordant if CHD was identical to the index case, and concordant for the group if belonging to a similar group of CHD.ResultsA recurrence of CHD was seen in 178 (2.7%) of 6,640 pregnancies. The referral numbers for sibling, maternal, or paternal CHD cases were 5,151, 1,119, and 370, respectively. Exact concordance was seen in 37% of cases (range 0% to 80%), and group concordance was seen in 44%. In families where there were two or more recurrences, the exact concordance rate was 55%. Exact concordance rates were particularly high for isolated atrioventricular septal defects (4 of 5 [80%]) and laterality defects (7 of 11 [64%]).ConclusionsThe concordance rates of different types of CHD vary widely. Accurate diagnosis of the index case is essential for reliable counseling on patterns of recurrence. Minor CHD in the index case does not exclude more severe disease in recurrences. There appears to be significant under-referral for fetal echocardiography in paternal CHD
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