Journal of Medical Genetics

Published by BMJ Publishing Group
Online ISSN: 1468-6244
Publications
Article
Pendred syndrome is an autosomal recessive disease characterised by congenital sensorineural deafness and goitre. The gene responsible for Pendred syndrome has been mapped to chromosome 7q31 in a 5.5 centimorgan (cM) interval flanked by D7S501 and D7S523. This interval was recently refined a to 1.7 cM interval located between D7S501 and D7S692. In the present study, we report linkage analysis data on a large consanguineous family genotyped with eight microsatellite markers located between D7S501 and D7S523. Complete cosegregation with the disease locus was observed with the loci analysed, which further supports locus homogeneity for Pendred syndrome and close linkage to this region. Haplotype analysis placed the Pendred syndrome gene between D7S496 and D7S2425 in a 0.8 cM interval. This additional refinement of the Pendred syndrome region will facilitate the construction of a physical map of the region and will help the identification of candidate genes.
 
Forest plots of random effects meta-analyses of datasets assessing the association between APOE SNPs rs429358 and rs7412 and MS risk in populations of European descent. The x-axis depicts the OR. Study-speci fi c ORs (black squares) and 95% CIs (CIs, lines) were calculated for each included dataset. The summary ORs and 95% CIs (grey diamonds) were calculated combining all datasets and after strati fi cation for published datasets, imputed GWAS datasets, and newly genotyped datasets as indicated. Exclusion of studies violating Hardy-Weinberg equilibrium in controls ( p<0.05, labelled with ‘ # ’ ) did not substantially change the meta-analysis results (data not shown). References to the published datasets listed in this fi gure can be found in the e-References. ANZgene, Australia and New Zealand Multiple Sclerosis Genetics Consortium; APOE , apolipoprotein E; CH, Switzerland; GWAS, genome-wide association studies; IMSGC, International Multiple Sclerosis Genetics Consortium; MS, multiple sclerosis; NL, Netherlands; SNPs, single nucleotide polymorphisms. 
Article
Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
 
Ability of the ultrasound examination to detect cystic fibrosis 
of cystic fibrosis and CF heterozygosity among fetuses with echogenic bowel in Brittany, France (1991-2000) 
Article
Cystic fibrosis (CF) is the commonest severe autosomal recessive disease that affects children in white populations, with an incidence varying from 1/2500 to 1/5000 (carrier rate 1/25 to 1/35).1 The disease, which is characterised by chronic pulmonary obstruction and infections, and by digestive disorders such as pancreatic insufficiency, is caused by mutations in a gene which encodes a protein called CFTR (cystic fibrosis transmembrane conductance regulator). The cloning of the CFTR gene in 19892–4 and the identification of more than 1000 mutations,5 with geographical and ethnic variations, have enabled prenatal testing for CF by direct detection of mutations. Initially, prenatal testing was only offered to families in which there was a previous history of CF. More recently, the medical assessment of pregnancy performed in some countries has allowed, through systematic ultrasound examinations, the prenatal diagnosis of bowel echogenicity, an abnormality suggestive of CF. The fetus can therefore become the proband in this disease. Fetal echogenic bowel, defined as bowel with sonographic density greater than that of the surrounding bone, is diagnosed in 0.2-1.8% of fetuses during routine ultrasound examination in the second trimester of pregnancy.6–10 This intestinal echogenicity was initially described as a normal variant, which usually disappeared at 20 weeks of gestation.11,12 More recently, it has also been associated with fetal abnormalities, such as chromosomal abnormalities,6,8,10,13–17 congenital infections,18–20 intestinal obstruction,20–22 and CF. In this latter case, it is probably the result of the malfunctioning of the CFTR protein leading to the dehydration of mucus secretions, which become viscous, obstruct the bowel lumen, and cause meconium ileus.23 The risk for CF in fetuses with echogenic bowel has been extensively studied6,9,10,13,16,20,21,24–30 and is shown …
 
Article
Editor—Alkaptonuria (AKU, OMIM 203500) is a rare disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO, EC 1.13.11.5).1 HGO catalyses the conversion of homogentisate (HGA) to maleylacetoacetate in the phenylalanine/tyrosine catabolic pathway.2 As a consequence, affected subjects excrete HGA in their urine, which becomes dark upon exposure to air. The medical interest in this condition stems from its association with ochronosis, or the deposition of a brownish pigment in connective tissues including cartilage, where its accumulation can produce a debilitating degenerative joint disease.3 AKU occupies a unique place in the history of human genetics because it was the first disorder to be described as a Mendelian recessive trait.4-6 Recent advances in the understanding of the molecular basis of AKU7-9 have verified that loss of function mutations in the HGO gene are responsible for the disease. A few mutations have been repeatedly detected in patients from different European countries. Since these mutations segregated with specific haplotypes, they should be considered to be old mutations that have spread throughout western Europe with migration. However, allelic heterogeneity is the main feature emerging from the above and other studies.7 9-12Most HGO mutations were found in just one family and did not involve CpG dinucleotides. Rather, a preferential occurrence in the CCC sequence motif and its inverted complement GGG has recently been reported.12 Furthermore, some AKU chromosomes escaped mutation detection within the HGO coding region, suggesting the existence of HGO alleles whose defect might be related to gene expression. To determine the extent of allelic heterogeneity in Italian patients, we started a systematic search of AKU families through announcements at relevant National Congresses. We present here the results leading to the identification of four novel mutations. Our data should facilitate future mutation screening …
 
Relative frequencies of CYP21 alleles in 50 southern Italian CAH chromosomes 
Part of the family pedigree showing informative markers from which the haplotypes were constructed. 
Article
Editor—Alkaptonuria (AKU) is a disorder of the catabolism of aromatic amino acids. A defect of homogentisate 1,2 dioxygenase (HGO) leads to an accumulation of homogentisic acid (HGA) and subsequently to deposition of polymerised HGA, a brown-black pigment, in connective tissue, primarily in cartilage.1 2This phenomenon is known as ochronosis. It results in debilitating arthropathy which typically becomes manifest in the fourth decade of life. Large amounts of HGA are excreted in the urine and cause its black discolouration upon oxidation. In 1891, homogentisic acid was first isolated by Wolkow and Baumann3 from the urine of an AKU patient from a remote area of the Black Forest in south western Germany. In 1902, Garrod, aware of this biochemical finding, observed the autosomal recessive mode of inheritance of AKU and thereby showed for the first time that mendelian laws also apply to human genetics.4 Garrod postulated that AKU results from an enzyme deficiency and introduced the concept of the “inborn error of metabolism”.5 Recently, the human gene encoding HGO was cloned by Fernadez-Canon et al .6Two different …
 
Article
A three-generation family with four patients affected by a novel mesomelic dysplasia was investigated for genome-wide DNA copy number variation profiles. This revealed a microduplication of a 1.0-Mb chromosomal segment at 2q31.1 spanning nine Homeo box D (HOXD) genes that co-segregated with the phenotype. Quantitative PCR analysis of a gene within this duplicated region showed consistent results. Mesomelic dysplasia Kantaputra type (MDK; MIM 156232),which shares some phenotypes with this family, has also been mapped to a chromosomal region comprising 2q31.1, raising the possibility that MDK and the condition observed in this family may be allelic.
 
Article
We describe a de novo apparently balanced reciprocal translocation t(6;12)(q16.2; q21.2) in an 18 month old girl with Shwachman syndrome, characterised by exocrine pancreatic insufficiency and bone marrow dysfunction. The cause of this syndrome is unknown, although autosomal recessive inheritance has been proposed. The translocation breakpoints in the present patient may be candidate regions for a gene responsible for Shwachman syndrome.
 
Article
Dyskeratosis congenita (DC) is a rare inherited disorder characterised by the early onset of reticulate skin pigmentation, nail dystrophy, and mucosal leucoplakia. In over 80% of cases bone marrow failure develops and this is the main cause of early mortality. The DC1 gene responsible for the X linked form (MIM 305000) of dyskeratosis congenita has been mapped to Xq28. In order to narrow the candidate gene region, genetic linkage analysis was performed in eight X linked pedigrees using a set of markers spanning Xq28. A maximum lod score of 5.31 with no recombinations was achieved with marker DXS1073. Two recombination events were identified; one of these uses X chromosome inactivation pattern analysis to determine carrier status and haplotype analysis to fine map the recombination breakpoint. The fine mapping of these recombination events has enabled the candidate gene region for X linked dyskeratosis congenita to be defined as the 1.4 Mb interval between Xq3274 and DXS1108.
 
Article
Large deletions of the NF1 gene region occur in approximately 5% of patients with neurofibromatosis type-1 (NF1) and are associated with particularly severe manifestations of the disease. However, until now, the genotype-phenotype relationship has not been comprehensively studied in patients harbouring large NF1 gene deletions of comparable extent (giving rise to haploinsufficiency of the same genes). We have performed the most comprehensive clinical/neuropsychological characterisation so far undertaken in NF1 deletion patients, involving 29 patients with precisely determined type-1 NF1 (1.4 Mb) deletions. Novel clinical features found to be associated with type-1 NF1 deletions included pes cavus (17% of patients), bone cysts (50%), attention deficit (73%), muscular hypotonia (45%) and speech difficulties (48%). Type-1 NF1 deletions were found to be disproportionately associated with facial dysmorphic features (90% of patients), tall stature (46%), large hands and feet (46%), scoliosis (43%), joint hyperflexibility (72%), delayed cognitive development and/or learning disabilities (93%) and mental retardation (IQ<70; 38%), as compared with the general NF1 patient population. Significantly increased frequencies (relative to the general NF1 population) of plexiform neurofibromas (76%), subcutaneous neurofibromas (76%), spinal neurofibromas (64%) and MPNSTs (21%) were also noted in the type-1 deletion patients. Further, 50% of the adult patients exhibited a very high burden of cutaneous neurofibromas (N>or=1000). These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.
 
Article
Williams-Beuren syndrome (WBS, OMIM 194050) is a microdeletion syndrome caused by hemizygosity for multiple genes in 7q11.23 including the elastin locus ( ELN ).1,2 The classical WBS phenotype comprises elastin arteriopathy (supravalvular aortic stenosis and/or peripheral pulmonary stenosis), connective tissue abnormalities (for example, abnormal joint mobility, hernia and diverticula, hoarse voice), and a particular facial appearance (supraorbital fullness, stellate pattern of the iris, short nose with long philtrum, full lips, and wide mouth). Other frequent features are growth and psychomotor retardation with muscular hypotonia, limited visuospatial cognition, and specific language as well as behavioural abnormalities (overfriendliness and anxiety disorders, hypersensitivity to sounds).3–5 Endocrine and metabolic disturbances (infantile hypercalcaemia) may occur. Despite at least 21 genes having been identified in the common 1.5 Mb deletion interval in humans,6 their individual contribution to the multisystem phenotype of WBS is unclear. So far, only the gene coding for elastin ( ELN ) has been proven to be causally involved7: ELN is deleted in all WBS patients with a microdeletion 7q11.23 who have been reported to date. However, hemizygosity for ELN alone does not cause WBS, but isolated supravalvular aortic stenosis (SVAS).8 Hence, haploinsufficiency for ELN is necessary but not sufficient for WBS. Molecular dissection of the WBS phenotype is hindered by the fact that over 95% of patients with the classical phenotype carry an apparently identical ~1.5 Mb deletion interval.9–11 This constant size is explained by non allelic-homologous recombination between duplicons flanking the deletion interval.12 The presence of these direct repeats is assumed to be a predisposing factor for the WBS microdeletion that occurs with a frequency of approximately 1 in 20 000 liveborn children.12 So far, several cases of either classical WBS or SVAS with or without cognitive deficits have been found to …
 
Article
X linked recessive idiopathic hypoparathyroidism (HPT) has been observed in two kindreds from Missouri, USA. Affected subjects, who are males, suffer from infantile onset of epilepsy and hypocalcaemia, which appears to be the result of an isolated congenital defect of parathyroid gland development; females are not affected and are normocalcaemic. The gene causing HPT has been previously mapped to a 7 cM interval, flanked centromerically by F9 and telomerically by DXS98, in Xq26-q27, and an analysis of mitochondrial DNA has established a common ancestry for these two kindreds. In order to define further the map location of HPT and thereby facilitate its isolation, we have undertaken linkage studies using polymorphic loci whose order has been established as Xcen - DXS1001 - DXS294 - DXS102 - F9 - DXS1232 - DXS984 - CDR1 - DXS105 - DXS1205 - DXS1227 - DXS98 - DXS52 - Xqter, within this region. Our results established linkage (lod score > 3) between HPT and eight of these 12 loci and indicated that the most likely location of HPT was within a 1.5 Mb interval flanked centromerically by F9 and telomerically by DXS984. Thus, the results of this study have helped to refine the map location of HPT, and this will facilitate the identification of this putative developmental gene and its role in the embryological formation of the parathyroids.
 
Article
Cystic fibrosis (CF, OMIM 219700) is one of the most common severe hereditary diseases occurring in white populations. It is characterised by considerable heterogeneity in the mutational spectrum and a diverse phenotypic presentation,1 which justifies extensive studies on the correlation between the cystic fibrosis transmembrane regulator ( CFTR ) genotype and the CF phenotype. Genotype-phenotype data are available especially for common genotypes,2 but information remains scarce or lacking for genotypes of compound heterozygotes with a rare mutation and homozygotes for a rare mutation.3 Among rare CFTR gene mutations, 1811+1.6kbA>G is practically absent in CF patients from other parts of France, but it is not rare in patients genotyped in the south west of France, occurring in fourth place after F508del, G542X, and N1303K. Its frequency is 3.4%4 and higher than 5% with reference to the number of CF chromosomes with a south western geographical origin.5 The mutation 1811+1.6kbA>G, located in intron 11 of the CFTR gene, is (with the mutation 3849+10kbC>T) one of the only two splicing mutations of the CFTR gene that generates a new exon (1811+1.6kbA>G creates a donor site, 3849+10kbC>T an acceptor site). Furthermore, it was previously ranked by Chillon et al 6 among class I mutations responsible for defective CFTR protein production and a severe CF phenotype. However, because it allows a reduced synthesis of normal protein, the mutation 1811+1.6kbA>G has also been reported in class V.7,8 According to the recent classification proposed by Welsh et al ,9 the mutation 1811+1.6kbA>G now belongs definitely to the “new” class I. The present report aims to study as well as possible the clinical severity of the mutation 1811+1.6kbA>G. The clinical data from 13 CF patients originating from the south west region of France and bearing 1811+1.6kbA>G (11 compound heterozygotes and two homozygotes) …
 
GeneHunter postscript graph of total LOD scores for the region of genetic linkage to FIHP on chromosome 2.  
Article
Familial isolated hyperparathyroidism (FIHP) is an autosomal dominantly inherited form of primary hyperparathyroidism. Although comprising only about 1% of cases of primary hyperparathyroidism, identification and functional analysis of a causative gene for FIHP is likely to advance our understanding of parathyroid physiology and pathophysiology. A genome-wide screen of DNA from seven pedigrees with FIHP was undertaken in order to identify a region of genetic linkage with the disorder. Multipoint linkage analysis identified a region of suggestive linkage (LOD score 2.68) on chromosome 2. Fine mapping with the addition of three other families revealed significant linkage adjacent to D2S2368 (maximum multipoint LOD score 3.43). Recombination events defined a 1.7 Mb region of linkage between D2S2368 and D2S358 in nine pedigrees. Sequencing of the two most likely candidate genes in this region, however, did not identify a gene for FIHP. We conclude that a causative gene for FIHP lies within this interval on chromosome 2. This is a major step towards eventual precise identification of a gene for FIHP, likely to be a key component in the genetic regulation of calcium homeostasis.
 
Article
Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36. In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36. Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.
 
Article
Two laboratories in the West Midlands have monitored 1000 `at risk' pregnancies. Of these 57% were referred for chromosomal indications and 43% for possible neural tube defects. The largest at risk groups (both 37%) were those mothers who had already had a pregnancy resulting in a baby with a neural tube defect (21% spina bifida and 16% anencephaly), and those who were referred because of the increased risk of Down's syndrome in pregnancies where the mother was over 35 years old. Six percent had already borne a child with Down's syndrome.
 
Article
The features of a child with osteogenesis imperfecta type III (OI III) resulting from the heterozygous substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen were studied. He was born at term with the clinical features of severe OI, including deep grey-blue sclerae. He had severe osteopenia and all long bones were smaller than normal with cortical thinning, metaphyseal expansion, poor metaphyseal modelling, and multiple fractures. However, the vertebrae, pelvis, and shoulder girdle were of normal shape and there were few rib fractures. Histological examination of the calvarium and tibial shaft showed woven bone without lamellar bone or Haversian systems. The shafts of the long bones were widened owing to repeated fractures. Progressive enlargement of the calvarium occurred between 3 and 4.5 months of age owing to bilateral chronic subdural haematomata and a large arachnoid cyst in the Sylvian fissure. The cyst was probably developmental in origin while the subdural collections were probably the result of perinatal skull trauma. The cyst and the subdural collections resolved following drainage but ventricular dilatation with normal cerebrospinal fluid pressure followed. The proband is the first reported case of OI with a glycine substitution by alanine in the pro alpha 2(I) chain of type I procollagen.
 
Article
The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
 
Screen shot of the Copy Number Variation Finder (CNVF) output using the optimised parameter set in patient 12. Note indication of the 17q and 22q confirmed deletions depicted in fig 2, and a duplication on chromosome 2 that was already present in the genomic-variation database. The lines flanking an aberration cluster give the flanking SNPs (separated by a semicolon for easy access to genome information on the respective aberration) in the University of California Santa Cruz genome browser. Columns contain the Copy Number Analysis Tool (CNAT) output information. Left to right: probe set, chromosome, physical position, call (ie genotype), single-point analysis copy number, single-point analysis p value, genomic smoothing algorithm copy number, genomic smoothing algorithm p value, loss of heterozygosity value. Note that the chromosomal position of SNPs given in the array data may differ from the actual genome browser information. The feature ‘‘homozygote only’’ means that SNP intensity values indicating a deletion are only labelled as deletion if the respective genotype is homozygous. 
Overview of detected aberrations verified by FISH or quantitative PCR
Examples of plots of +/2 log 10 GSA p values calculated with Affymetrix Copy Number Analysis Tool V.2 for copy numbers of SNPs of the Affymetrix GeneChip Human Mapping 100K SNP array in patient 12 using a Gnuplot program. Genotypes of individual SNPs are indicated by coloured bars at the bottom (magenta, homozygous; blue, heterozygous; brown, no call). Upper: plot of +/2 log 10 GSA p values for SNPs covering chromosome 17 in patient 12, with a 0.4 Mb de novo deletion in 17q21.31 indicated by Copy Number Variation Finder (CNVF) parameter set A1 and confirmed by fluorescence in situ hybridisation (arrow). Note magenta stretch of homozygosity corresponding to the deleted region. Lower: plot of +/2 log 10 GSA p values for SNPs covering chromosome 22 in the same patient showing a 250 kb inherited deletion in 22q11.23 indicated by CNVF parameter set A2 and confirmed by FISH (arrow). Note that the resolution of the plot does not allow determination of the number of SNPs passing the thresholds of ¡2.5. This is achieved by the CNVF, which indicated in this specific case that 16 SNPs passed the threshold in the 17q21.31 deletion and 7 in the 22q11.23 deletion (fig 1). *Duplication identified in 11.5% of patients, which overlaps with a deletion at 28.1 Mb described as a normal variant.
Overview of clinical findings in patients with de novo aberrations
Overview of results of molecular karyotyping with the 100K array using the Copy Number Variation Finder (CNVF) with parameter sets (A, C, E) A1 and (B, D, F) A2. (A, B) White bars, deletions; black bars, duplications. (A) Set A1 revealed 10 unique deletions, 23 unique duplications and 9 different recurrent duplications; (B) set A2 revealed 42 unique deletions, 151 unique duplications, 53 different recurrent deletions and 314 recurrent duplications. (C, D) Number of patients with a particular number of aberrations. (C) Using the stringent parameter set A1, 51 patients showed no aberration, whereas 53 of the 104 patients showed at least 1 of 92 aberrations (average of 0.9 aberrations per patient in the total study group); (D) A2 indicated at least 1 of 1792 aberrations in every patient, with an average of 17.2 aberrations per patient. (E, F) Size distribution of aberrations indicated by sets (E) A1 and (F) A2.
Article
Using array techniques, it was recently shown that about 10% of patients with mental retardation of unknown origin harbour cryptic chromosomal aneusomies. However, data analysis is currently not standardised and little is known about its sensitivity and specificity. We have developed an electronic data analysis tool for gene-mapping SNP arrays, a software tool that we call Copy Number Variation Finder (CNVF). Using CNVF, we analysed 104 unselected patients with mental retardation of unknown origin with a genechip mapping 100K SNP array and established an optimised set of analysis parameters. We detected deletions as small as 20 kb when covered by at least three single-nucleotide polymorphisms (SNPs) and duplications as small as 150 kb when covered by at least six SNPs, with only one false-positive signal in six patients. In 9.1% of patients, we detected apparently disease-causing or de novo aberrations ranging in size from 0.4 to 14 Mb. Morphological anomalies in patients with de novo aberrations were equal to that of unselected patients when measured with de Vries score. Our standardised CNVF data analysis tool is easy to use and has high sensitivity and specificity. As some genomic regions are covered more densely than others, the genome-wide resolution of the 100K array is about 400-500 kb for deletions and 900-1000 kb for duplications. The detection rate of about 10% of de novo aberrations is independent of selection of patients for particular features. The incidental finding in two patients of heterozygosity for the 250 kb recurrent deletion at the NPH1 locus, associated with autosomal recessive juvenile nephronophthisis, which was inherited from a healthy parent, highlights the fact that inherited aberrations might be disease-related even though not causal for mental retardation.
 
Article
Several genes involved in the DNA damage response and in maintaining genomic stability have emerged as breast cancer susceptibility genes. These include BRCA1 and BRCA2, as well as other genes with smaller contributions to breast cancer aetiology, such as TP53 , CHEK2 , and ATM . Germline mutations in BRCA1 and BRCA2 increase sensitivity to DNA damage and decrease cellular capacity to repair double strand DNA breaks through homologous recombination.1–3 Interestingly, DNA damage induces activation of ATM (ataxia-telangiectasia mutated), which performs a central role in relaying signals that orchestrate DNA repair.4 People with heterozygous nonsense mutations in ATM appear to display increased susceptibility to breast cancer.5–7 Besides rapidly phosphorylating BRCA1,8 activated ATM also phosphorylates p53 and CHEK2 (CHK2, hCDS1), which have been implicated in breast cancer predisposition. Germline mutations in TP53 or CHEK2 cause Li-Fraumeni syndrome, a multiple cancer phenotype syndrome, which features early onset breast cancer.9,10 Recently, it was found that germline mutations in CHEK2 also increase the relative risk for breast cancer outside the Li-Fraumeni syndrome.11,12 Given …
 
Article
Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
 
Haplogroup distribution for 897 cases of type 2 diabetes and 1010 controls 
Article
Mitochondria play a central role in the secretion of insulin by pancreatic beta-cells, and pathogenic mutations of mitochondrial DNA (mtDNA) can cause diabetes. The aetiology of type 2 diabetes has a strong genetic component, raising the possibility that genetic variants of mtDNA alter the risk of developing the disorder. Recent studies have produced conflicting results. By studying 897 UK cases of type 2 diabetes and 1010 population-matched controls, it is shown that European mtDNA haplogroups are unlikely to play a major role in the risk of developing the disorder.
 
Article
There have been growing calls for more education in genetics for the public and in schools. However, studies of the public, school children, and those who have received genetic counselling show that understanding of scientific genetics is very limited. A hypothesis to explain this limited understanding is proposed and tested. It is argued that there is a widespread lay knowledge of inheritance which conflicts in a number of aspects with scientific explanations and which impedes the assimilation of the latter. It is suggested that this lay knowledge is derived from concepts of the social relationships of kinship. Concepts of kinship ties are sustained by everyday social activities and relationships which may make them resistant to change. A prediction which follows from the hypothesis that the lay understanding of genetics is derived from concepts of family and kinship relationships is that closeness in genetic terms will be determined by the closeness of the family ties of social relationship and social obligation. While the proportion of genes shared with parents, children, and sibs is, on average, the same, kin relationships and obligations are much stronger between parents and children than between sibs. The hypothesis was tested in a questionnaire study of two samples of adult women (n = 64 and n = 113) and one of social science students (n = 73). In all three groups a higher proportion of subjects gave the correct response for the proportion of shared genes with a father and child than with a sister, uncle, or grandmother. In the cases of sisters and uncle (and grandmother), there was a consistent tendency to underestimate the degree of genetic connection as predicted by the hypothesis. Answers to other questions are consistent with the hypothesis. The fundamental implications of the hypothesis for genetic education in the clinic and classroom are outlined.
 
Subject characteristics in the analysed samples of the two surveys 
Age-BMI relationship by gender and survey: mean BMI for each 5 year age group for men (solid line) and for women (broken line) (A) survey S3 (1994/1995), (B) survey S4 (1991/2001). It is clear that this relationship is homogeneous for both surveys. An intercept can be observed for men versus women and a secular trend with higher BMIs in the later survey (S4) can be seen particularly for the 25-60 year olds. 
Article
The melanocortin-4-receptor gene (MC4R) is part of the melanocortinergic pathway that controls energy homeostasis. In a recent meta-analysis, the MC4R V103I (rs2229616) polymorphism was shown to be associated with body weight regulation. Although no functional differences between the isoleucine comprising receptor and the wild type receptor have been detected as yet, this meta-analysis of 14 case-control studies reported a mild negative association with obesity (odds ratio (OR) 0.69, p = 0.03). However, evidence in a large population based study in a homogeneous population and a significant estimate of the change in quantitative measures of obesity is still lacking. We analysed the data of two surveys of a white population with the same high quality study protocol, giving a total of 7937 participants. By linear regression, we found a significant decrease of 0.52 body mass index (BMI) units (95% confidence interval (CI) -0.02 to -1.03, p = 0.043) for carriers of the heterozygote rs2229616G/A genotype, which was observed in 3.7% of the participants. Logistic regression yielded a significantly negative association of the MC4R variant with "above average weight" (BMI > or = median BMI) yielding an OR of 0.75 (95% CI 0.59 to 0.95 p = 0.017). We obtained similar results comparing obese (BMI > or =30 kg/m2, World Health Organization results for 1997) with non-obese (BMI < 30 kg/m2) participants. The results were found for both sexes and each survey separately, and did not depend on the modelling of age, sex, or survey effects. Our study confirms previous findings of a meta-analysis that the relatively infrequent G/A genotype of the V103I MC4R polymorphism is negatively associated with above average weight and obesity in population based original data of 7937 participants, and extends previous findings by showing for the first time a significantly lower BMI in individuals carrying the infrequent allele of this MC4R variant.
 
TGM1 mutations reported in this investigation and previous studies. (A) The 44 germline TGM1 mutations identified. Asterisks denote the 22 novel mutations identified; mutations identified in both this and previous studies are not marked with asterisks. (B) The 50 previously reported germline TGM1 mutations that were not identified in the present study. Blue, missense; green, nonsense; red, frameshifts, orange, putative splice site.  
TGase-1 alignments showing amino acid sequence comparisons among human, dog and mouse. Boxes indicate amino acid residues within the TGase-1 domains. Yellow characters indicate the amino acid positions where missense mutations were identified. Triangles represent active site residues (Cys 377 , His 436 , Asp 459 ). The 22 TGM1 missense mutations identified in our cohort are marked.  
Article
Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI. The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA. Methods: Germline mutations in TGM1 were identified in 55% (57/104) of patients with ARCI. Arginine residues in TGase-1 were mutated in 39% (22/57) of patients overall and 54% (20/37) of those with missense mutations. In total, 55% (12/22) of missense mutations were within CpG dinucleotides and 92% (11/12) of these mutations were C-->T or G-->A transitions. The genotype-phenotype investigation found that ARCI with TGM1 mutations was significantly associated with presence of collodion membrane at birth (p = 0.006), ectropion (p = 0.001), plate-like scales (p = 0.005) and alopecia (p = 0.001). Patients who had at least one mutation predicted to truncate TGase-1 were more likely to have more severe hypohidrosis (p = 0.001) and overheating (p = 0.0007) at onset of symptoms than were those with exclusively TGM1 missense mutations. A logistic model was developed, which predicted that individuals with collodion membrane, alopecia and/or eye problems are about four times more likely to have TGM1 mutations than patients without these findings. This is the largest investigation of patients with ARCI to date. It expands the TGM1 mutation spectrum and confirms that despite genetic and phenotypic heterogeneity in ARCI, TGM1 is the main causative gene for this disorder. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of CpG dinucleotides.
 
Article
We report studies on two German-American persons with systemic amyloidosis. Affected subjects presented with carpal tunnel syndrome in the sixth decade of life followed by peripheral neuropathy. DNA analysis of the transthyretin gene showed a new point mutation which is responsible for substitution of valine for isoleucine at position 107 of the transthyretin molecule.
 
Article
Cartilage-hair hypoplasia (CHH) is an autosomal recessive form of metaphyseal chondrodysplasia characterised by short limbed short stature, hypoplastic hair growth, and impaired cell mediated immunity and erythrocyte production. The syndrome is exceptionally prevalent among the Finns and among the Old Order Amish in the United States; sporadic cases have been reported from other countries. An epidemiological and genetic study of CHH in Finland showed 107 patients, 46 males and 61 females, in 85 families. Eighteen of them had died, seven before the age of 1 year. The living patients ranged in age from 1 to 51 years, median 21 years. The incidence was estimated to be 1:23,000 live births. Consanguinity was found in two families and interfamilial relationships in 20 families. Geographical distribution of the birth places of the patients and their great grandparents showed accumulation in a small area in western Finland and regional clusters were seen in other parts of the country as well. The result of the segregation analysis was in accordance with recessive inheritance with reduced penetrance.
 
Comparison of either 1078 del T or GS51D mutation with AFS08/1F508 using continuous variables 
Article
Apart from the high frequency of the delta F508 mutation (81.81%) in Breton cystic fibrosis chromosomes, one mutation, 1078 del T, is also observed frequently (4.96%) in this group, in comparison with the rest of the French where it occurs with a frequency of 0.57%. These two mutations account for more than 86.5% of the total CF mutations identified on Breton chromosomes. We have conducted an unblinded retrospective analysis of 25 patients with the 1078 del T mutation and compared their phenotypes with those of a group of 70 delta F508 homozygous patients. Both groups of patients had the same ethnic origin and were regularly attending the same CF centre in Brittany, which makes this sample highly homogeneous despite the small size. The 1078 del T mutation appeared to be associated with severe presentation of the disease with, however, a trend to reduced mortality and less Pseudomonas aeruginosa colonisation.
 
Article
Ageing is associated with chronic, low grade inflammatory activity leading to long term tissue damage, and systemic chronic inflammation has been found to be related to mortality risk from all causes in older persons.1 Also, the genetic constitution of the organism interacting with systemic inflammation may cause defined organ specific illnesses. Thus, age related diseases such as Alzheimer’s disease (AD), Parkinson’s disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis, are initiated or worsened by systemic inflammation, suggesting the critical importance of unregulated systemic inflammation in the shortening of survival in humans.1–3 Accordingly, proinflammatory cytokines are believed to play a pathogenetic role in age related diseases, and genetic variations located within their promoter regions have been shown to influence the susceptibility to age related diseases, by increasing gene transcription and therefore cytokine production.3,4 Conversely, genetic variations determining increased production of anti-inflammatory cytokines or decreased production of proinflammatory cytokines have been shown to be associated with successful ageing, suggesting a role for the control of the inflammatory state in the attainment of longevity. As recently reported, the distribution of +874T→A interferon(IFN)-γ,5 −174C→G IL-6,6 and −1082G→A interleukin(IL)-107 single nucleotide polymorphisms (SNPs) has been shown to be different in centenarians than in younger people.5–7 The +874T allele, involved in high production of the proinflammatory cytokine IFN-γ, was found less frequently in centenarian women than in control women.5 Also, the proportion of subjects homozygous for the G allele at the −174 IL-6 locus, characterised by high serum levels of the proinflammatory cytokine IL-6, was significantly decreased in centenarian men.6 Conversely, the presence of the −1082 GG genotype, suggested to be associated with high production of the anti-inflammatory cytokine IL-10, was significantly increased in centenarian men in comparison with younger male subjects.7 These …
 
Clinical features of the family. (A) Pedigree showing transmission of the phenotype through three generations. (B) Facial appearance of family members (from left to right) II-3, II-5 (unaffected), III-3, and II-2 (Photograph with family’s permission) . 
Comparison of 59 splice sites
Article
Sequence variations within splice sites may pose problems in the interpretation of their pathogenic effect, especially when these variations occur outside the highly conserved /gt (donor or 5′ site) and ag/ (acceptor or 3′ site) consensus dinucleotides that immediately flank most exons. A commonly used method to evaluate the probable effect of a sequence variation on splicing is to calculate the Shapiro-Senapathy (SS) score, which is based on the extended splice site consensus sequence.1–3 Here we present a sequence variation in a 5′ splice site of the gene encoding fibroblast growth factor receptor type 2 ( FGFR2 ) that maintains a consensus nucleotide at the variant position, but nevertheless causes a switch to the use of a cryptic 5′ splice site within the upstream (IIIc) exon. This variant is present in three generations of a family and manifests with mild features of Crouzon syndrome. Following informed consent blood samples were collected from members of the family pedigree shown in fig 1. DNA was isolated by proteinase K treatment and phenol chloroform extraction. RNA was also extracted from the blood of affected individual II-2 and cDNA synthesised by standard techniques. Figure 1 Clinical features of the family. (A) Pedigree showing transmission of the phenotype through three generations. (B) Facial appearance of family members (from left to right) II-3, II-5 (unaffected), III-3, and II-2 (Photograph with family’s permission) . Mutation screening of exons IIIa and IIIc of FGFR2 4 was undertaken in DNA from the proband using WAVE (3500HT; Transgenomic) denaturing high performance liquid chromatography.5 Sequencing was performed with Big Dye (version 3) on an ABI 3100 DNA sequencer. Oligonucleotide hybridisation was carried out on cDNA derived from individual II-2. Reverse transcriptase PCR (RT-PCR) using primers 4F and 9R located respectively in FGFR2 exons 6 and 12 (exon numbering according to Kan et …
 
Analysis of amplified DNA from exon 5 in the family of the proband. Each pair of tracks shows the amplified product undigested on the left and digested with TaqI on the right. Tracks 1 and 2 are from the father, tracks 3 and 4 the affected girl, tracks 5 and 6 an unaffected sister, tracks 7 and 8 an unaffected brother, and tracks 9 and 10 the mother. 
Article
We studied DNA from 29 families with at least one member with ornithine carbamoyl transferase (OCT) deficiency and have found a mutation in the TaqI site within exon 5 of the OCT gene in a female presenting at the age of 21 months. Hybridisation with site specific oligonucleotides shows that the mutation is a C to T substitution resulting in a glutamine for arginine substitution at amino acid 109.
 
Distribution of types of LRD in 82 reported cases. 
Article
Epidemiological and genetic variables in limb reduction defects (LRD) were analysed during the years 1978 to 1987 in a case control study in Emilia Romagna, northern Italy. During the observation period, 83 neonates out of 173,109 consecutive births had LRD (4.8 per 10,000). Cases were divided into five subgroups: transverse, intercalary, longitudinal, split, and multiple types of LRD. Of all cases, 64% were upper limb, 21% lower limb, and 15% both. Coexisting non-limb malformations were found in 10 cases (12%), five with recognised syndromes and five with other associated defects. About 7.2% of first degree relatives had defects involving the skeletal system. In two cases the mother had the same type of LRD (a split). No recurrence among sibs was observed. Risk factors correlated with LRD were found to be low birth weight (2500 g or less), vaginal bleeding, and threatened abortion.
 
Article
In vitro studies on skin cultures established from 49 members from Kindred 109, in whom the Gardner syndrome was first delineated, showed that increased in vitro tetraploidy occurred only in those cultures derived from branches with the full expression of the Gardner gene (colorectal polyps with multiple extracolorectal benign tumours) and not in those derived from branches showing only extracolorectal lesions. Increased in vitro tetraploidy appeared to identify only those family members at risk who had, or would ultimately be expected to show, full expression of the Gardner gene including colorectal polyps which become malignant.
 
Correlations between the ABCC8/KCNJ11 genotype and the radiopathological diagnosis 
Characteristics of ABCC8 and KCNJ11 mutations 
Article
Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
 
Article
Pachytene quadrivalents are described in a male heterozygous for a balanced reciprocal translocation between the long arms of chromosomes 10 and 11. The break points of the translocation occur at 10q23 and 11q24. The main chromomere patterns of the bivalents correspond to the main G bands in mitosis and are sufficiently pronounced to allow the identification of bivalents 10 and 11 in normal spermatocytes.
 
Clinicalfeatures ofthe proband. (a, b) Frontal view and facial dysmorphism ofproband at I I l _year 9 months. (c) Abnormal hair pattern with multiple whorls in the neonatal period. 
Article
Partial duplications of 10p and 13q in association with partial deletions of other chromosome segments have been variously reported. We describe here a female child with multiple congenital abnormalities and combined partial duplications of 10p and 13q resulting from a 3:1 segregation of a maternal t(10;13)(p13;q22). In comparing the phenotypic features of the two chromosome imbalances, the expression of features typical of partial duplication 10p appeared more pronounced.
 
Results of FISH of t(10;13) No of cells with FISH signal* 
Renal histology of the patient: a low power field magnification (A) and a high powerfield magnification (B) with PAS staining. anatomical abnormalities or vesicoureteral reflux. To evaluate the cause of proteinuria, percutaneous kidney biopsy was performed. Microscopic examination of the biopsy disclosed striking atrophy of the proximal and distal renal tubules and interstitial fibrosis but with little inflammatory cell infiltration of the interstitium (fig 1A). Three of eight glomeruli examined showed focal segmental sclerosis with mild mesangeal proliferation (fig 1 B). Immunofluorescence studies did not show any deposit of immunoglobulins, fibrinogen, or complement.
Partial G banded karyotype of the patient. 
Metaphases from the patient showing FISH with YAC 29C-D5. (A) Chromosomes stained with propidium iodide showing hybridisatioin of the probe to the normal chromosome 10 (arrowhead), the derivative chromosome 10 (small arrow), and the derivative chromosome 13 (large arrow). (B) The same metaphase as in (A) stained with DAPIfor chromosome identification. 
Article
We describe a 5 year old boy with a de novo t(10;13) translocation and optic nerve coloboma-renal disease (ONCR). On the basis of GTG banding analysis of prometaphase chromosomes, the patient's karyotype was interpreted as either 46,XY,t(10;13)(q24.3;q12.3) or t(10;13) (q25.2;q14.1). Fluorescence in situ hybridisation (FISH) studies using a YAC clone containing the PAX2 gene and YAC clones adjoining FRA10B at 10q25.2 showed that the 10q breakpoint had occurred just within the PAX2 gene and was proximal to FRA10B. These FISH results suggest that the translocation causes a disruption of the PAX2 gene and leads to ONCR, in agreement with the recent reports of PAX2 mutations in two unrelated families with ONCR. Furthermore, we refined the regional mapping of the human PAX2 gene to the junction of bands 10q24.3 and 10q25.1.
 
Article
Five members of our study family were carriers of a balanced insertion (10;5) (q22;q13;q22). One of the children had psychomotor retardation and malformations resulting from a partial trisomy of the proximal long arm of chromosome 5, having received the maternal der(10). Amniocentesis identified another case of partial proximal trisomy in a fetus of a subsequent pregnancy. This clinical and family study is compared with two other published cases of proximal trisomy 5q.
 
Article
We report a case of monosomy for the distal region of the short arm of chromosome 10 (p13----ter) associated with trisomy for the terminal region of the long arm of chromosome 5 (q35.2----ter) that had originated from adjacent 1 segregation of a maternal reciprocal balanced translocation (5;10)(q35.2;p13). We review the clinical findings of previously reported cases of both partial monosomy for 10p and of partial trisomy for 5q, but to our knowledge there are no previous reports of the effects of these two chromosome anomalies together. Clinically our patient showed features typical of partial monosomy for 10p (including hypothyroidism) rather than partial trisomy 5q.
 
Article
An infant with features of trisomy 10p syndrome was found to have an abnormal chromosome 10: 46, XY, rec(10), dup p, inv(10) (p11q26) mat. The infant's mother was heterozygous for a pericentric inversion involving chromosome 10 (46, XX, inv (10) (p11q26). The infant's derivative chromosome was apparently produced by meiotic recombination between the inversion chromosome and its normal homologue.
 
Article
We present a case with a small extra ring chromosome which was found in 66% of lymphocytes on routine cytogenetic examination. FISH analyses, using centromere specific and single copy probes, showed that the extra ring chromosome was derived from the most proximal part of 10p, close to the centromere. The patient has a unilateral cleft lip and palate, mild dysmorphic features, and mild mental retardation. Only a limited number of extra ring chromosomes have been characterised so far. To our knowledge, this is the first reported patient with an extra ring chromosome derived from chromosome 10p.
 
Article
A female infant with karyotype 46,XX,rec(10),dup p inv(10)(p11.2q25.2)mat is presented. She had both duplication of 10p and deletion of distal 10q, but only had the constellation of specific features characteristic of duplication of 10p.
 
Article
Partial monosomy 10p is a rare chromosomal disorder characterised by frontal bossing, micrognathia, congenital heart defects, vesicoureteral abnormalities, and developmental delay. This is the first report to describe seizures not associated with hypocalcaemia, as well as cortical atrophy and decreased white matter volume on magnetic resonance imaging, in a patient with documented partial monosomy 10p. The neuroradiographic abnormalities found in this patient provide a first step towards understanding the aetiology of the developmental delay and ventriculomegaly associated with this chromosomal abnormality.
 
Article
A familial four breakpoint complex chromosomal rearrangement involving chromosomes 9, 10, and 11 was ascertained through a child with dysmorphic features, hypertrophic cardiomyopathy, and hypotonia. A cryptic insertion, invisible in G banded chromosomes was identified by fluorescence in situ hybridisation (FISH) using chromosome specific libraries. Possible mechanisms of its formation as well as karyotype-phenotype correlation are discussed.
 
Frequency of 22q11 deletion in 100 CTHD patients 
Article
Heart defects are among the most common congenital anomalies, occurring in approximately 1% of newborn populations.1 Conotruncal heart defects (CTHD), which account for 50-60% of all congenital heart malformations, are known to have a strong genetic component. They occur either as an isolated malformation or in association with extracardiac anomalies. In particular, CTHD constitute a cardinal component of branchial arch syndromes, such as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), and conotruncal anomaly-face syndrome (CTAFS). The wide phenotypic spectrum includes cardiac defects, abnormal facies, thymic hypoplasia or aplasia, cleft palate, and hypoparathyroidism.2, 3 The presence of a characteristic 3 Mb microdeletion on chromosome 22q11 in 70-90% of these patients indicates a common genetic aetiology.4, 5 Haploinsufficiency for the Tbx I transcription factor in the critical region appears to be responsible for the aortic arch defects …
 
Patient aged 2 months and 12 years 8 months. (Photographs reproduced with permission.) 
Features of the DGS/VCFS and the HDR syndrome spectrum of nine patients with structural abnormality of 10p 
Molecular characterisation of 10p deletions in 10 patients with features of DGS/VCFS syndrome and HDR syndrome. (A) The results of fine mapping of breakpoint intervals by FISH with seven PACs show that the deletion of MEG does not overlap with the deletion of WON and that the breakpoint of WON maps at least 200-300 kb distal from DGCR2. Deleted PACs are indicated as open boxes, non-deleted PACs as closed boxes. (B) The patients indicated with a three letter acronym were studied by us. Data from patients MEG, AMS, and MAR have been reported previously. 3 Clinical data of WAB have been reported previously 2 and WON is a new patient. The molecular and clinical data from the other five patients were taken from published reports. Patient CH92-092 was reported by Gottlieb et al, 5 DW was reported by Dasouki et al, 6 and C1 and C2 are cases 1 and 2 described by Van Esch et al. 11 The features of the patients are given according to the acronyms of the DGS/VCFS spectrum (CATCH=Cardiac defect, Anomaly of face, Thymic hypoplasia, Cleft palate, Hypocalcaemia/Hypoparathyroidism) and HDR syndrome (Hypoparathyroidism, Deafness, Renal anomaly). Distances of markers were taken from the LDB map (http://cedar.genetics.soton.ac.uk/pub/chrom10/map.html). The regions for DGS (DGCR2) and HDR syndrome (HDR1) are indicated. Solid horizontal bars indicate regions not deleted in the patients, breakpoint intervals are drawn as hatched bars, and deleted regions as open bars. 
Article
Partial monosomy 10p is a rare chromosomal condition and a significant proportion of patients show features of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). A critical haploinsufficiency region for DGS/VCFS was defined on 10p (DGCR2). We performed molecular deletion analysis of two further patients with partial monosomy 10p, who showed hypoparathyroidism, deafness, and renal dysplasia or renal insufficiency, but no cardiac defect, cleft palate, or reduced T cell levels. Previously, the combination of hypoparathyroidism, deafness, and renal dysplasia has been proposed to represent a specific syndrome (MIM 146255) under the acronym HDR. In addition to the two patients in this report, at least four published cases with partial monosomy 10p show the triad of HDR and 14 other patients present with at least two of the three features. We therefore conclude that HDR syndrome can be associated with partial monosomy 10p. Based on molecular deletion analysis and the clinical data, we suggest that the DGS/VCFS phenotype associated with 10p deletion can be considered as a contiguous gene syndrome owing to haploinsufficiency of two different regions. Hemizygosity of the proximal region, designated DGCR2, can cause cardiac defect and T cell deficiency. Hemizygosity of the distal region, designated HDR1, can cause hypoparathyroidism and in addition sensorineuronal deafness and renal dysplasia/insufficiency or a subset of this triad.
 
Article
Since its description in 1965, distal 10q trisomy has become recognised as a well defined, although rare syndrome, almost always the result of an unbalanced translocation. Typical features consist of psychomotor delay, a distinctive dysmorphic appearance, growth retardation, and, in some cases, cardiac, renal, and ocular abnormalities.
 
Top-cited authors
Dafydd Gareth Evans
  • The University of Manchester
Charis Eng
  • Cleveland Clinic
Anne De Paepe
  • Ghent University
Jean-Pierre Fryns
Robert M.W. Hofstra