The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom‐designed 244K array‐CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra‐skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non‐specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X‐linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

ABSTRACT Objectives Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. Methods Two different questionnaires were produced. Results Fifty geneticists filled in the questionnaire. Twenty‐two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty‐four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. Conclusion This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request. © 2012 John Wiley & Sons, Ltd.

The phenotype of mosaic variegated aneuploidy (MVA) syndrome is characterized by severe microcephaly, growth deficiency, mental retardation, and mild physical anomalies. The MVA syndrome is associated with mosaicism for several different aneuploidies involving many different chromosomes with or without premature centromere division (PCD). To date 28 cases of MVA syndrome have been reported. We report the first case of MVA syndrome without microcephaly. The clinical features in our patient included craniofacial dysmorphic features, growth retardation, and developmental delay. Cytogenetics analyses and FISH studies showed multiple aneuploidy with trisomy 18, 19, and 8, respectively in blood lymphocyte and fibroblasts without PCD. This case is compared with the other of MVA syndrome previously reported in literature. From this case report, we suggest that microcephaly is not mandatory for the diagnosis of MVA syndrome.

British Journal of DermatologyVolume 152, Issue 1 p. 191-193 X-linked recessive ichthyosis in a girl: strategy for identifying the causal mechanism C. Thauvin-Robinet, C. Thauvin-Robinet Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorD. Lambert, D. Lambert Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorG. Vaillant, G. Vaillant Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorP. Caillier, P. Caillier Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorA. Donzel, A. Donzel Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorV. Cusin, V. Cusin Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorF. Huet, F. Huet Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorJ.-R. Teyssier, J.-R. Teyssier Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorF. Mugneret, F. Mugneret Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorL. Faivre, L. Faivre Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this author C. Thauvin-Robinet, C. Thauvin-Robinet Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorD. Lambert, D. Lambert Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorG. Vaillant, G. Vaillant Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorP. Caillier, P. Caillier Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorA. Donzel, A. Donzel Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorV. Cusin, V. Cusin Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorF. Huet, F. Huet Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorJ.-R. Teyssier, J.-R. Teyssier Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorF. Mugneret, F. Mugneret Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this authorL. Faivre, L. Faivre Département de Génétique, Hôpital Le Bocage, Dijon, France *Service de Dermatologie, Faculté de Médecine, Dijon, France†Service d'Endocrinologie, Dijon, France E-mail: christel.thauvin@chu-dijon.frSearch for more papers by this author First published: 17 January 2005 https://doi.org/10.1111/j.1365-2133.2005.06367.xCitations: 10Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume152, Issue1January 2005Pages 191-193 RelatedInformation

Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.

Cloacal exstrophy is a rare malformation, belonging to a spectrum of birth defects, which, in order of severity, includes phallic separation with epispadias, pubic diastasis, bladder exstrophy, and cloacal exstrophy. This malformation overlaps the OEIS complex (O = omphalocele, E = bladder exstrophy, I = imperforate anus, S = spinal defects). The etiology of cloacal exstrophy is unknown to date. It may result from either a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. We report an infant with cloacal exstrophy, exomphalos, right kidney agenesis, ambiguous external genitalia, and axial hypotonia. The karyotype showed a de novo unbalanced translocation between the long arm of chromosome 9 and the long arm of chromosome Y resulting in a 9q34.1‐qter deletion. Reviewing the literature, we did not find any observation of cloacal exstrophy associated with a structural chromosomal abnormality. The steroidogenic factor 1 (SF1) gene, included in the deleted region, was a good candidate gene but no pathogenic mutation was found by direct sequencing. We hypothesize that another gene, expressed early in embryogenesis and responsible for cloacal exstrophy, is present in the 9q34.1‐qter region. © 2003 Wiley‐Liss, Inc.

Spinal muscular atrophy (SMA) is a common autosomal recessive disease. SMA is linked to the 5q13 locus in 95% of patients, and in at least 98% of them, the SMN1 homozygous deletion is found. Compound heterozygous patients, who have an SMN1 deletion associated with a subtle mutation, appear undeleted with the common molecular diagnostic test that detects only the homozygous absence of SMN1. In these patients, mutation screening in SMN1 is hampered by the presence of several copies of the highly homologous SMN2 gene. Here, we present a rapid and reliable strategy for detecting SMN mutations using long-range PCR, which avoids cloning and cDNA analysis. Using this method, we found 10 mutations, including five mutations never reported previously and five recurrent mutations; some of them are probably population-specific. Marker analysis of the 5q13 locus in these mutations showed common haplotypes, supporting the hypothesis of a common ancestor rather than a hot spot sequence. We also evaluate the suitability of automated SSCA and DHPLC for mutation scanning.

Overgrowth is rarely associated with chromosomal imbalances. Here, we report on a male foetus presenting with overgrowth and additional material on the short arm of one of the chromosome 15 in 12% of lymphocytes and 50% of amniotic cells. Parents' karyotypes were normal, indicating a de novo origin for this unbalanced rearrangement. Complementary studies using cytogenetic and FISH studies showed that this additional material resulted in a 15q25‐qter trisomy and confirmed the presence of three copies of the insulin‐like growth factor 1 receptor ( IGF1R ) gene, included in the trisomic region. Autopsy performed after termination of pregnancy revealed isolated overgrowth and absence of visceral malformations. The possible mechanisms and origins for the formation of this mosaic pure trisomy are complex. The present observation emphasises the hypothesis that the overgrowth phenotype, frequently reported in patients with trisomy including the 15q26 region, might be causally related to a dosage effect of the IGF1R gene, as well as the importance of chromosome analysis in patients with overgrowth. It also confirms that the overgrowth is of prenatal onset in those observations. Copyright © 2004 John Wiley & Sons, Ltd.

The Fragile X syndrome is the most common cause of inherited mental retardation. Clinical features are neither specific nor constant and molecular diagnosis is thus widely used since the characterization of the causal mutation in 1991. The aim of this project was to study the evolution of Fragile X diagnosis in France. A preliminary study of the efficiency of screening for the Fragile X mutation in mentally retarded probands with no previous familial diagnosis was done in the Strasbourg's laboratory with a comparison between data from 1991–1994 and 1997–2000 (Biancalana et al. [2002: 1ières Assises de Génétique Humaine et Médicale: 95p]). This study showed an improvement in the use of the Fragile X testing regarding the probands' age at diagnosis and the recruitment of sporadic and female cases. To avoid possible bias in clinical referrals and to evaluate the situation nation wide, this study was enlarged to 28 of the 30 laboratories involved in the Fragile X diagnosis in France from 1997 to 2001 (20,816 probands tested, data representative of 95% of the national screening activity). Median age at diagnosis decreased from 9.2 to 5.8 (average 16–11.6y) between the 1991–1994 and the 1997–2001 studies. Over this period, 477 new families were diagnosed with Fragile X, representing 2.8% of tested male probands (417/14,867) and 1.0% of tested female probands (60/5,949). Forty one percent of positive cases corresponded to probands with a familial history of mental retardation, compared to 66% in the initial (1991–1994) study. We also discuss issues concerning premutations discovered in affected individuals and in females with premature ovarian failure (POF). © 2004 Wiley‐Liss, Inc.

Spinal muscular atrophy (SMA) is the second most frequent autosomal recessive disease, with a prevalence of 1 in 6000 live born infants.1 It is characterised by degeneration of motor neurones of the anterior horn of the spinal cord, leading to symmetrical muscular weakness and atrophy. The International SMA Consortium classification2 defines several degrees of severity in the SMA phenotype, depending on the age of onset and motor development milestones. Type I SMA, Werdnig-Hoffmann I disease, is the most severe form with onset within 6 months of birth. Patients are unable to sit up and have serious respiratory dysfunction. Type II SMA is the intermediate form with onset within the first 2 years; children can sit up but are unable to walk. The clinical course is variable. Type III (also called Kugelberg-Welander disease) begins after 2 years of age and usually has a chronic evolution. Children can stand and walk unaided at least in infancy. Adult form (type IV) is the mildest, with onset after 30 years of age; few cases have been reported and its prevalence is not accurately known. Spinal muscular atrophy is linked to locus 5q13 in more than 95% of patients.3–6 The critical region, containing several genes including the survival motor neurone ( SMN ) gene, is inverted and duplicated. Homozygous deletion of SMN1 , located in the telomeric position, accounts for the disease in 98% of these cases and has been reported in infantile, intermediate, and adult onset disease.7–10 Linkage analysis in families with SMA shows large de novo deletions in 2% of patients.11–13 SMN2 is a highly homologous gene located in the centromeric duplicated region.7,14 Most of the SMN1 transcripts are full length, whereas most of the SMN2 transcripts lack exon 7. In fact, a nucleotide substitution …

Dyschondrosteosis (DCS) has been recently ascribed to mutations of the SHOX gene on the pseudoautosomal region of the X and Y chromosomes.1 2 Most cases are accounted for by large scale deletions3-7 and only two point mutations have been hitherto identified in exon 4 (R195 X and Y199X1 2). Here, we show that point mutations in various regions of the SHOX gene also play an important role in the pathogenesis of the disease.A total of 22 affected subjects belonging to eight families were included in the study. Inclusion criteria for affected status were short stature (2 SD below normal) with short forelimbs …

The aim of this study of 44 cases of tetralogy of Fallot was to assess the echocardiographic aspects and the prognosis with respect to associated abnormalities and the potential evolution in utero. Group I, tetralogy of Fallot with other abnormalities (N = 27: 2 valvular agenesis, 26.5 5.3 weeks), had genetic anomalies in 18 of the foetus (10 trisomies including 5 trisomy 21, 5 structural abnormalities including 2 micro-deletions 22q11 in the two cases of valvular agenesis, and one deletion of chromosome 8p23.1, 3 mendelian syndromes) and other abnormalities in 9 cases. Hypoplasia of the pulmonary artery was present in 60% of cases with a non-dilated aorta in 72%, infundibular hypertrophy in 33% and 2 evolutions to pulmonary atresia. Aspect of "isolated" ventricular septal defect were observed in 20% of cases. Survival was 10%. In Group II, tetralogy of Fallot was isolated (N = 17, including 2 pulmonary valve agenesis, 31 +/- 6 weeks) (p < 0.01 versus Group I). Pulmonary artery hypoplasia was observed in 50% of cases with dilatation of the aorta and infundibular hypertrophy in all and in one a postnatal progression towards pulmonary atresia. A correlation between growth of the pulmonary artery and gestational age was found in 5 foetus out of 9 studied sequentially (p between 0.03 and 0.007) and between age at first surgery and size of the pulmonary artery (r = 0.80, p = 0.001). Survival was 84%. The risk of malformation (61%) and the prenatal potential evolution of this disease justifies continuous follow-up of all cases of tetralogy of Fallot, high resolution karyotyping and postnatal evaluation in a specialized centre.

Acromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive disorder belonging to the group of acromesomelic dysplasias. AMDM is characterised by severe dwarfism with shortening of the middle and distal segments of the limbs. An AMDM gene has recently been mapped to human chromosome 9p13-q12 by homozygosity mapping in four consanguineous families. Here, we show linkage of the disease gene to chromosome 9p13-q12 in four of five consanguineous AMDM families and its exclusion in a fifth family with two children affected with a mild form of the disease. This study suggests that genetic heterogeneity accounts for the variable clinical and radiological severity of AMDM.