Prenatal microarray comparative genomic hybridization: Experience from the two first years of activity at the Lyon university-hospital.

OBJECTIVES: This study aims to describe how microarray comparative genomic hybridization (aCGH) has shifted to become a prenatal diagnosis tool at the Lyon university-hospital. MATERIALS AND METHODS: This retrospective study included all patients who were referred in the 3 pluridisciplinary centers for prenatal diagnosis of the Lyon university-hospital and who received a prenatal aCGH between June 2013 and June 2015. aCGH was systematically performed in parallel with a karyotype, using the PréCytoNEM array design. RESULTS: A total of 260 microarrays were performed for the following indications: 249 abnormal ultrasounds (95.8%), 7 characterizations of chromosomal rearrangements (2.7%), and 4 twins with no abnormal ultrasounds (1.5%). With a resolution of 1 mega base, we found 235 normal results (90.4%), 23 abnormal results (8.8%) and 2 non-returns (0.8%). For the chromosomal rearrangements visible on the karyotype, aCGH identified all of the 12 unbalanced rearrangements and did not identify the 2 balanced rearrangements. Among the fetuses with normal karyotypes, 11 showed abnormal microarray results, corresponding to unbalanced cryptic chromosomal rearrangements (4.2%). CONCLUSION: Transferring aCGH to a prenatal diagnosis at the Lyon university-hospital has increased the detection rate of chromosomal abnormalities by 4.2% compared to the single karyotype.

Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome.

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens.

BACKGROUND: Most infertile males with congenital bilateral absence of vas deferens (CBAVD) carry mutations on the cystic fibrosis transmembrane conductance regulator gene and may express mild cystic fibrosis (CF) symptoms. Barriers to paternity for these men can now be overcome by assisted reproduction. Our aims were to investigate the CF-related phenotype and clinical outcome for 50 patients with CBAVD seen at a CF adult centre between 1992 and 1999. METHODS AND RESULTS: The investigation of the patients included screening for 22 CF mutations and identification of the poly-T variant of intron 8, sweat testing, clinical investigation for CF-related extra-genital manifestations, and genetic counselling. CFTR mutations were detected on 56 alleles of the 50 patients. A total of 15 (30%) was compound heterozygote and 26 (52%) heterozygote. In all, 38% of the patients had a positive sweat test. Four patients were diagnosed with typical CF not detected previously. Twenty-one patients became fathers following ICSI (eight cases), artificial insemination by donor or IVF with sperm donor (seven cases) or through adoption (six cases). A mail survey allowed the identification of CF-related clinical symptoms. Information on the occurrence of CF-related symptoms was obtained for 58.5% of patients: in the absence of initial symptoms, no new clinical signs were reported. CONCLUSION: Patients diagnosed with CBAVD need genetic counselling before assisted reproduction. Even when no wish for paternity is expressed, CF gene screening should be associated with at least a sweat test and clinical evaluation because of possible mild forms of CF disease. Medical follow-up did not reveal any new symptoms.

[Cystic fibrosis. Fertility and reproduction]. / Fertilité et reproduction.

Fertility and reproduction are now frequent questions for cystic fibrosis adult patients. Females are sometimes subfertile because of abnormal cervical mucus viscosity or anovulatory cycles. After genetic counseling and evaluation of respiratory prognosis, assisted reproduction can be proposed. Fertility is frequently normal and contraception should be proposed. Oral contraception appears to be safe. Pregnancy in cystic fibrosis women should be undertaken after genetic counseling and clinical evaluation; the prognosis for the mother is not modified for patients with stable pulmonary status and FEV1 up to 30% of predicted with correct nutritional status. Preterm delivery is frequent. Usual therapeutics should be continued unless ursodeoxycholic acid or nonsteroidal antiinflammatory drugs. Usual antipseudomonas antibiotics can be used; pulmonary exacerbations have to be treated early. Almost all cystic fibrosis men are infertile because of congenital bilateral absence of vas deferens (CBAVD). CBAVD can revealed incomplete cystic fibrosis phenotypes associated with specific genotypes. After genetic counseling, intracytoplasmic injection after epididymal puncture can be proposed. In all cases, it is important to evaluate the life prognosis, before pregnancy or paternity and to propose genetic counseling, essentially depending on the genotype of the spouse.

Trisomy 17 mosaicism in amniotic fluid cells not found at birth in blood but present in skin fibroblasts.

This article describes a case of fetal trisomy 17 mosaicism found in amniotic fluid cells in one of two bichorial biamniotic twins without any sonographic anomaly. The extra chromosome 17 was absent from cord blood cells at birth but present on karyotype and in situ hybridization in cultured fibroblasts from skin biopsy. Clinical examination showed a few mild dysmorphic features and a moderate neurological involvement which may rather be related to prematurity. It therefore seemed important to obtain the karyotype on fibroblasts when a trisomic cell line was found in amniocentesis and not confirmed on blood lymphocytes, even in the absence of dysmorphic features. This should help to differentiate a real mosaic from a mosaic restricted to extra-fetal tissues.

[Male infertility caused by bilateral agenesis of the vas deferens: a new clinical form of cystic fibrosis?]. / Stérilité masculine par agénésie bilatérale des canaux déférents: une nouvelle forme clinique de mucoviscidose?

Congenital bilateral absence of vas deferens causes male excretory infertility and represents 1 to 2% of male infertility. Because of a genotypic similarity with cystic fibrosis, the possible in vitro fertilization with epididymal sperm requires careful genetic counselling. We studied genotype, sweat chloride concentration, respiratory function tests, sinus abnormalities, pancreatic and hepatic functions in 22 subjects with congenital bilateral absence of vas deferens. Among them, four were compound heterozygotus, all of them with the R117H mutation. Ten had a positive sweat test, one of them also being compound heterozygotus. Congenital bilateral absence of vas deferens and double mutation or positive sweat test led to high probable cystic fibrosis diagnosis in 13 subjects. Six subjects were heterozygotus for one cystic fibrosis mutation, criterium which is not sufficient for cystic fibrosis diagnosis; five of them had sinus abnormalities, present in 11 of the 22 subjects. Only three patients had no mutation nor sweat chloride abnormalities. This work confirms the high frequency of cystic fibrosis mutations in males with congenital bilateral absence of vas deferens, with a higher frequency of positive sweat test than in other publications, and a high frequency of sinus abnormalities. This monosymptomatic phenotype of cystic fibrosis suggests new hypotheses for a relationship between genotype and phenotype.

Diagnostic criteria for cystic fibrosis in men with congenital absence of the vas deferens.

The high frequency of cystic fibrosis (CF) mutations in males with absence of vas deferens supported the hypothesis of a primarily genital phenotype of CF disease. To consider the idea of an attenuated form of CF, we investigated 14 men with congenital bilateral aplasia of the vasa deferentia. All patients were consulting for infertility and none was known to have CF. The median age was 30.5 years (range, 20-38 yr). DNA analysis for 22 CF mutations showed at least 1 mutation in 10 patients (71%), whereas the CF carrier frequency is only 4% in the general population. Three compound heterozygotes were identified, all carriers of the R117H mutation. The sweat test was considered positive in 6 patients (43%), and a high frequency of radiologic evidence of sinus disease (8 patients) and of elevated antibodies to Pseudomonas (8 patients) was found. Only 2 patients were free of all these criteria for CF disease. This study strengthens the hypothesis that absence of vas deferens is an attenuated form of CF. We propose a combination of tests including DNA study, computerized tomographic scan of the paranasal sinuses, and testing of anti-Pseudomonas antibodies when the sweat test is inconclusive.

[Incidence of malformations of the urinary tract in the Rhône-Alps area. Apropos 1357 cases of affected infants identified over a 7-year period (1976-1982)]. / Incidence des malformations des voies excrétrices urinaires (V.E.U.) dans la région Rhône-Alpes. A propos de 1357 cas d'enfants atteints, identifiés pendant une période de 7 ans (1976-1982).

The authors use a regional birth defect registry computerized since 1976 January 1st. They describe the incidence of urinary tract defects, excluding renal dysplasias. Their classification shares this group of malformations in 3 parts: those included in a multiple defects association, identified or not, those associated with renal defects, and the isolated urinary tract defects.