Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants.

The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

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.

Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans.

CONTEXT: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. OBJECTIVE: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. DESIGN AND SETTING: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. PATIENTS AND METHODS: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. MAIN OUTCOME MEASURES: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. RESULTS: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. CONCLUSIONS: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.

BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays.

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging.

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.

INTRODUCTION: Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. METHODS: We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG Ia, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. RESULTS: Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). CONCLUSIONS: Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency.

Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years' experience and impact on prenatal diagnosis.

BACKGROUND: Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child. METHODS: The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an immunoreactive trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated. FINDINGS: Of the 343,756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2.32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%). INTERPRETATION: We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.

Fronto-otopalatodigital osteodysplasia: clinical evidence for a single entity encompassing Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2, and frontometaphyseal dysplasia.

Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression in carrier females and comprises typical facial anomalies and a generalized bone dysplasia with osteodysplastic changes, brachydactyly, and impaired survival. Recently several other severe malformations were reported in the condition. Melnick-Needles syndrome is an X-linked dominant disorder. Affected males are usually sporadic cases. The exceptional males born to symptomatic women present with a lethal disorder comprising generalized osteodysplasia, deficiency of the first ray, and facial anomalies strikingly similar to those of otopalatodigital syndrome type 2. We report here on three boys with classical, severe, and lethal otopalatodigital type 2 syndrome, and three boys with severe (lethal) Melnick-Needles syndrome, born to affected mothers. We suggest that otopalatodigital type 1 and 2, Melnick-Needles syndrome and frontometaphyseal dysplasia, sharing many clinical manifestations and a similar mode of inheritance, are variants of the same condition: fronto-otopalatodigital osteodysplasia. The relationships to similar syndromes (i.e., Saint-Martin-Gardner-Morrisson syndrome, serpentine fibula syndrome, atelosteogenesis type 3, boomerang dysplasia, and Yunis-Varon syndrome) are discussed.

Collaborative study of mosaic tetrasomy 12p or Pallister-Killian syndrome (nineteen fetuses or children).

The difficulties in the diagnosis of Pallister-Killian syndrome are illustrated in this study of nineteen fetuses and children. Diagnosis based on clinical appearance alone is often difficult due to the broad spectrum of clinical anomalies not specific to this syndrome. Due to mosaicism, it is altogether necessary to examine several tissues for the presence of tetrasomy 12p, including circulating lymphocytes in which mosaicism can be as low as 1-3%, amniocytes, chorionic cells and skin fibro-blasts in which mosaicism ranges from 6-100%. When highly suspected on ultrasound examination, the diagnosis recommends prenatal cytogenetic studies because survivors are severely mentally retarded. All the cases are sporadic with only a single preliminary report of recurrence. The cytogenetic diagnosis is therefore helpful in order to reassure family members in regard to genetic counseling.

Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz and the lethal acrodysgenital syndromes.

UNLABELLED: The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease. CONCLUSION: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders.

No evidence of genetic heterogeneity in dominant optic atrophy.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease causing a variable reduction of visual acuity with an insidious onset in the first six years of life. It is associated with a central scotoma and an acquired blue-yellow dyschromatopsia. A gene for dominant optic atrophy (OPA1) has recently been mapped to chromosome 3q in three large Danish pedigrees. Here, we confirm the mapping of OPA1 to chromosome 3q28-qter by showing close linkage of the disease locus to three recently reported microsatellite DNA markers in the interval defined by loci D3S1314 and D3S1265 in four French families (Zmax = 5.13 at theta = 0 for probe AFM 308yf1 at locus D3S1601). Multipoint analysis supports the mapping of the disease gene to the genetic interval defined by loci D3S1314 and D3S1265. The present study provides three new markers closely linked to the disease gene for future genetic studies in OPA.

Neonatal screening for cystic fibrosis: result of a pilot study using both immunoreactive trypsinogen and cystic fibrosis gene mutation analyses.

We have evaluated a two-tier neonatal cystic fibrosis (CF) screening of immunoreactive trypsinogen (IRT) followed by CFTR gene mutation analysis using a systematic scanning of exons 7, 10, and 11, and, if necessary, by direct DNA sequencing. Over an 18-month period we screened 32,300 neonates born in the western part of Britanny. The first tier, involving IRT screening at 3 days of age, utilizes a low elevation of the trypsinogen level (600 ng/ml), which is highly sensitive. The second tier, which corresponds to the exhaustive screening for mutations in three exons of the gene, is highly specific for this population (Britanny). The false positive rate is very low, and no false negatives have been reported to date. This strategy has allowed the identification of five novel alleles (V322A, V317A, 1806 del A, R553G, G544S).

[Reflections on 10 years of medically induced abortions in Ille-et-Vilaine]. / Réflexions sur 10 ans d'interruptions médicales de grossesse (IMG) en Ille-et-Vilaine.

The medical files of 532 patients who underwent medically induced abortion over a 10-year period (1982-1991) in the French department of Ille-et-Vilaine were studied in order to evaluate the indications and outcomes. Among the patients, 358 resided in the department (67%). Comparatively with the number of births during the 10-year period, there was a relative increase in the number of medically induced abortions from 3.5/1000 to 5.5/1000. This parameter was taken into consideration for the interpretation of a parallel decrease in the perinatal mortality during the same period, from 5.9/1000 to 5.1/1000. There was a maternal indication in 91 cases which correspond to the former category of therapeutic induced abortions. There was a clear increase in 1991 corresponding to abortions induced because of extremely premature rupture of the membranes which were formerly allowed to continue to dead births. Foetal indications were frequent: 441 cases (83%). Exogenous causes were lower (15.6%), particularly due to the disappearance of indications resulting from maternal irradiation. For indications related to infection, the vaccination against rubella and improved prenatal diagnosis resulted in the disappearance of rubella as an indication during the last three years of the study and a clear decrease in the number of toxoplasmosis indications. There were few indications due to maternal infection by human immunodeficiency virus (4 cases). Chromosomal abnormalities were the main cause of medically induced abortion among the foetal indications (27.7%).(ABSTRACT TRUNCATED AT 250 WORDS)