Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

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.

Increased aneuploidy rates in spermatozoa of a male carrier of a trisomy 18 mosaicism.

Semen analysis of a 31-year-old infertile man showed a severe oligoteratozoospermia. Karyotyping of peripheral blood lymphocytes showed a 47,XY,+18[13]/46,XY[16] mosaicism. Cultured skin fibroblasts, right and left jugal smears showed 3, 50 and 65% trisomic cells respectively. The aim of the study was to evaluate the aneuploidy rates of chromosomes X, Y, 13, 18 and 21 and the diploidy rate in his spermatozoa by fluorescence in situ hybridization. The rate of disomy 18 was significantly increased in the spermatozoa of the patient (0.68%) compared to the control group (0.06%). A statistically significant difference in the rates of disomy for chromosome 13 (0.46% vs. 0.14%) and the gonosomes (0.78% vs. 0.24%) and diploidy (0.93% vs. 0.34%) was also found between the patient and the control group. However, no significant difference was observed for chromosome 21 (0.34% vs. 0.15%). Our results show evidence of a generalized perturbation of the meiotic mechanism that could lead to an increased risk for a mosaic trisomy 18 infertile male of producing offspring with aneuploidy that is not only on account of the father's mosaicism, but also more particularly because of severe oligoteratozoospermia.

Endocrine function in a 48,XXYY adult with type 2 diabetes: case report with a review of the literature.

We present the clinical, biological, endocrinal and psychological characteristics of a 48,XXYY adult. The 43-year-old male examined is the first reported case of this XY polysomy concomitant with type 2 diabetes. Endocrine investigations suggested dysfunction of Leydig and Sertoli cells whereas the pituitary function appeared normal. We compare the phenotypic, behavioral and pathological features of the syndrome in our patient with other reports in the literature.

In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History.

Niemann-Pick type C (NPC) disease is a recessive disorder that results in unesterified cholesterol accumulating in the lysosomal and late endosomal system. It is caused by mutations in NPC1 or NPC2 genes and leads to systemic and neurodegenerative symptoms. Few cases of prenatal presentation of NPC have been reported and only two cases in the absence of previous family history, indicating the diagnosis is particularly difficult in such a situation. We report a prenatal diagnosis of NPC in a couple without family history. An ultrasound screening at 22 weeks of gestation (WG) detected fetal ascites and hepatomegaly, which were still present at 25, 27, and 29 WG, and a splenomegaly progressively appeared. No placentomegaly or other signs of hydrops fetalis were observed. The diagnostic of NPC was prenatally confirmed by a filipin test and NPC1 sequencing and multiplex ligation-dependent probe amplification assay which revealed a maternal missense mutation (c.2608T>C; p.Ser870Pro) and a paternal deletion of exons 5 to 25. This additional prenatal case of NPC suggests that even in the absence of family history, fetal ascites associated with splenomegaly but no hydrops should nonetheless arouse suspicion concerning this disease as a possible diagnosis.

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus [FGS2]?

FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.

A gene for FG syndrome maps in the Xq12-q21.31 region.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Etiology, prognosis and management of nuchal cystic hygroma: 25 new cases and literature review.

OBJECTIVE: To develop an algorithm for the prenatal management of patients when a cystic hygroma is diagnosed by ultrasonography. METHODS: We report a personal series of 25 cases diagnosed between 10 and 23 weeks gestation and a review of the literature comprising a total of 999 cases. We focused on the etiologies and the value of various prognostic factors in the management of cystic hygromas. These include karyotype, alpha-fetoprotein levels, sonographic findings in the fetus and within the hygroma itself, and natural history. RESULTS: According to the literature, fetal chromosomal abnormalities were associated with cystic hygromas in 62% of the cases. Turner's syndrome remains the most common (33%) but Down's syndrome, Trisomy 18 and Trisomy 13 are not rare (15, 7 and 2%). Others have Mendelian abnormalities. The prognosis remains gloomy. The literature reports that only 9% of cases result in healthy children with normal karyotypes. The remaining 91% are either terminated (89%) or liveborn (2%), but with chromosome abnormalities or various malformations. CONCLUSION: The prognostic factors associated with a poor outcome are an abnormal karyotype and associated structural malformations. Resolution of the hygroma by 20 weeks gestation suggests a good prognosis, but is not definitive. All other factors evaluated do not appear to be of prognostic value at this time. Careful analysis of these prognostic factors is very important to identify the small percentage of normal children and to advise parents effectively for a future pregnancy.

Are t(X;Y) (p22;q11) translocations in females frequently associated with Madelung deformity?

We report a female with a de novo 46,X,der(X)t(X;Y) (p22;q12) translocation who presented with short stature, mild clinical features of Turner syndrome and a Madelung deformity. It appears that some particular radiological and/or clinical skeletal features are common in females carrying X-Y translocation. Based on the corresponding papers and on clinical findings of our patient we discuss the significance of Madelung deformity encountered in X-Y translocations, dyschondrosteosis and Turner syndrome.

[Prenatal outcome of sex chromosome anomalies diagnosed during pregnancy: a retrospective study of 47 cases]. / Devenir prénatal des anomalies des chromosomes sexuels diagnostiquées pendant la grossesse. Analyse rétrospective de 47 cas]

OBJECTIVE: To study the circumstances of discovery and the prenatal outcome of sex hormone anomalies diagnosed by invasive prenatal techniques during pregnancy and analyze which factors could be implicated in the parents' choice to terminate or carry on with pregnancy. METHODS: We reviewed retrospectively 47 cases of sex chromosome anomalies diagnosed and managed in our prenatal diagnosis unit over a 9-year period between January 1, 1990 and December 31, 1998. Only cases karyotyped in our laboratory and with a complete follow-up were considered. RESULTS: Cytogenic findings were mainly turner syndrome (n=25) and Klinefelter syndrome (n=12). The other karyotypes were the following: 47, XXX (n=6), 47, XYY (n=2), and 49, XXXXY (n=2). Among the 47 pregnancies, 11 (23.4%) were carried to term. The rate of pregnancy termination (68.1%) was high. The decision to terminate varied depending on the abnormal karyotype: 88% for Turner syndrome, 42% for Klinefelter syndrome, 33% for 47, XXX, 50% for 47, XYY and 100% for 49, XXXXY. The pregnancy termination rate was significantly higher when one or more abnormal ultrasound findings was present (92.3% vs 41.2%, p<0.01). CONCLUSION: Our study confirms that termination rates remain high in case of sex hormone anomalies. Associated ultrasonographic findings play a major role in the parents' choice to terminate or carry on with the pregnancy. It would appear that the development of consensual guidelines in pluridisciplinary fetal medicine centers can help reduce the disparities currently observed among French centers in the management of fetuses with sex chromosome anomalies.

Fetal intracerebral hemorrhage and cataract: think COL4A1.

The COL4A1 gene encodes the alpha1 chain of type IV collagen, a crucial component of nearly all basement membranes. Mutations in COL4A1 were first associated with cerebral microangiopathy and familial porencephaly. Recently, several authors have reported mutations in COL4A1 as a Mendelian cause of prenatal onset intracranial hemorrhage (ICH). We report two cases of prenatal ICH associated with cataract and suggest that COL4A1 mutation should be envisaged in fetuses with prenatal ICH, especially in the presence of lens abnormalities at ultrasound examination.

Binder phenotype in mothers affected with autoimmune disorders.

OBJECTIVE: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. PATIENTS AND METHODS: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. RESULTS: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. CONCLUSION: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes.

Influence of ultrasonographers training on prenatal diagnosis of congenital heart diseases: a 12-year population-based study.

OBJECTIVE: Since 1998, French multidisciplinary prenatal diagnosis centers (CPDPN) offer a training opportunity to first-level screening sonographers. This study measures the impact of this training on prenatal detection rates of congenital heart diseases (CHDs). METHODS: We analyzed the sensitivity of screening sonographers by comparing CHD prenatal diagnoses and CHDs observed after birth in the area of Angers from 1994 to 2006. Two groups of sonographers were compared, those who attended the training (n=19) and those who did not (control group. n=21). The evolution of CHD detection rate was compared between two successive periods of 6 years each. RESULTS: Of 947 CHDs, 438 (46%) were detected prenatally. The control group sensitivity was 16 versus 37% for the sonographers who had attended the training course (p<0.001).Between the two study periods, detection rates for all CHDs and significant CHDs remained unchanged in the control group, whereas they improved significantly in the other group (respectively 54% vs 33% and 75% vs 38%, p<0.05). CONCLUSION: This study supports the hypothesis of a beneficial effect of CPDPN on prenatal diagnosis of CHDs. These centers not only fulfill their primary purpose but also operate as learning centers in which screening sonographers may improve their practice.

Prenatal diagnosis of absence of the septum pellucidum associated with septo-optic dysplasia.

Septo-optic dysplasia (SOD; De Morsier syndrome) is a rare congenital disorder characterized by the absence of the septum pellucidum (SP), hypoplasia of the optic chiasma and nerves, and various types of hypothalamic-pituitary dysfunction. We report on two fetuses with absence of the SP diagnosed by ultrasound examination at 29 and 30 gestational weeks. In the first case the diagnosis of SOD was suspected in utero and confirmed postnatally; to the best of our knowledge this is the first report of the prenatal diagnosis of SOD. In the second case absence of the SP appeared to be isolated and no visual or endocrine impairment were detected after birth.

Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.

BACKGROUND: Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis. OBJECTIVE: To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies. METHODS: Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies. RESULTS: Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits. CONCLUSIONS: Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.

High resolution chromosome analysis and in situ hybridization on amniotic fluid for diagnosis of a cryptic translocation.

We report a cryptic translocation ascertained in a family after the birth of a mentally retarded proband. High resolution chromosome examination revealed that the father had a subtle translocation between chromosome 5 and chromosome 13, 46, XY, t(5;13) (q35.2;q34). Two specific, non-routine techniques were associated for prenatal diagnosis: high resolution cytogenetic studies on the amniotic fluid and fluorescent in situ hybridization with YACs as specific telomeric probes. The fetus had the same cryptic translocation as his father.

Stable anterior anchoring of the oocyte nucleus is required to establish dorsoventral polarity of the Drosophila egg.

In Drosophila, dorsoventral polarity is established by the asymmetric positioning of the oocyte nucleus. In egg chambers mutant for cap 'n' collar, the oocyte nucleus migrates correctly from a posterior to an anterior-dorsal position where it remains during stage 9 of oogenesis. However, at the end of stage 9, the nucleus leaves its anterior position and migrates towards the posterior pole. The mislocalisation of the nucleus is accompanied by changes in the microtubule network and a failure to maintain bicoid and oskar mRNAs at the anterior and posterior poles, respectively. gurken mRNA associates with the oocyte nucleus in cap 'n' collar mutants and initially the local secretion of Gurken protein activates the Drosophila EGF receptor in the overlying dorsal follicle cells. However, despite the presence of spatially correct Grk signalling during stage 9, eggs laid by cap 'n' collar females lack dorsoventral polarity. cap 'n' collar mutants, therefore, allow for the study of the influence of Grk signal duration on DV patterning in the follicular epithelium.