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Gervasini C.,University of Milan | Grati F.R.,TOMA Advanced Biomedical Assays S.p.A. | Lalatta F.,Clinical Genetic Unit | Tabano S.,University of Milan | And 11 more authors.
Genetics in Medicine | Year: 2010

Purpose: The Mayer-Rokitansky-Küster-Hauser syndrome is defined as congenital aplasia of müllerian ducts derived structures in females with a normal female chromosomal and gonadal sex. Most cases with Mayer-Rokitansky- Küster-Hauser syndrome are sporadic, although familial cases have been reported. The genetic basis of Mayer-Rokitansky-Küster-Hauser syndrome is largely unknown and seems heterogeneous, and a small number of cases were found to have mutations in the WNT4 gene. The aim of this study was to identify possible recurrent submicroscopic imbalances in a cohort of familial and sporadic cases with Mayer-Rokitansky-Küster-Hauser syndrome. Methods: Multiplex ligation-dependent probe amplification was used to screen the subtelomeric sequences of all chromosomes in 30 patients with Mayer-Rokitansky-Küster-Hauser syndrome (sporadic, n = 27 and familial, n = 3). Segregation analysis and pyrosequencing were applied to validate the MLPA results in the informative family. Results: Partial duplication of the Xpter pseudoautosomal region 1 containing the short stature homeobox (SHOX) gene was detected in five patients with Mayer-Rokitansky-Küster-Hauser syndrome (familial, n = 3 and sporadic, n = 2) and not in 53 healthy controls. The duplications were not overlapping, and SHOX was never entirely duplicated. Haplotyping in the informative family revealed that SHOX gene duplication was inherited from the unaffected father and was absent in two healthy sisters. Conclusions: Partial duplication of SHOX gene is found in some cases with both familial and sporadic Mayer-Rokitansky-Küster-Hauser type I syndrome. © 2010 Lippincott Williams & Wilkins.


Gervasini C.,University of Milan | Mottadelli F.,University of Milan | Ciccone R.,University of Pavia | Castronovo P.,University of Milan | And 8 more authors.
European Journal of Human Genetics | Year: 2010

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess. © 2010 Macmillan Publishers Limited All rights reserved.


Smith H.,University of Birmingham | Smith H.,University College London | Galmes R.,University Utrecht | Gogolina E.,University College London | And 24 more authors.
Human Mutation | Year: 2012

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apical-basolateral polarity regulator (VIPAR). Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients with ARC do not survive past the first year of life. We report two patients presenting with a mild ARC phenotype, now 5.5 and 3.5 years old. Both patients were compound heterozygotes with the novel VPS33B donor splice-site mutation c.1225+5G>C in common. Immunoblotting and complementary DNA analysis suggest expression of a shorter VPS33B transcript, and cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function). This study provides the first evidence of genotype-phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype. We have established an interactive online database for ARC (https://grenada.lumc.nl/LOVD2/ARC) comprising all known variants in VPS33B and VIPAR. Also included in the database are 15 novel pathogenic variants in VPS33B and five in VIPAR. © 2012 Wiley Periodicals, Inc.


Dai J.,Center for Genomic Medicine | Dai J.,Nanjing University | Kim O.-H.,Ajou University | Cho T.-J.,Seoul National University | And 34 more authors.
Journal of Medical Genetics | Year: 2010

Background: Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.


Unger S.,University of Lausanne | Gorna M.W.,Austrian Academy of Sciences | Le Bechec A.,Swiss Institute of Bioinformatics | Do Vale-Pereira S.,University of Lausanne | And 20 more authors.
American Journal of Human Genetics | Year: 2013

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth. © 2013 The American Society of Human Genetics.


Huber C.,University of Paris Descartes | Wu S.,University of California at Los Angeles | Kim A.S.,University of California at Los Angeles | Sigaudy S.,Clinical Genetic Unit | And 12 more authors.
American Journal of Human Genetics | Year: 2013

Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-kB activation pathway is involved in the pathogenesis of the skeletal ciliopathies. © 2013 by The American Society of Human Genetics. All rights reserved.


Renault F.,University Paris Est Creteil | Baudon J.-J.,University Pierre and Marie Curie | Galliani E.,Hopital Armand Trousseau | Flores-Guevara R.,University Paris Est Creteil | And 3 more authors.
Muscle and Nerve | Year: 2011

Introduction: We evaluated the role of electromyography (EMG) in assessing orofacial neurological dysfunction in 81 infants with Pierre Robin sequence (PRS). Methods: Needle EMG of muscles of the face, tongue, and soft palate, and blink responses were recorded. A two-channel EMG recorded sucking and swallowing during bottle feeding. Results: Neurogenic EMG signs were detected in facial or oral muscles in 17 of 24 associated PRS and 1 of 57 isolated PRS cases (P < 0.0001). Soft palate muscles showed low-amplitude traces in 41.4% of patients who required two surgical steps for cleft palate repair and 18.5% of those who required only one step. Regarding EMG study during bottle feeding, patients with moderate or severe abnormalities of oral/pharyngeal coordination required more prolonged enteral feeding than patients with mild abnormalities or normal coordination (P = 0.002). Conclusion: Combined EMG methods were useful in the treatment of infants with PRS. EMG detection of cranial nerve involvement strongly suggests an associated form of PRS. © 2011 Wiley Periodicals, Inc.


Nishimura G.,Tokyo Metropolitan Kiyose Childrens Hospital | Dai J.,RIKEN | Dai J.,Nanjing University | Lausch E.,University Hospital Freiburg | And 14 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

Recent discoveries have established the existence of a family of skeletal dysplasias caused by dominant mutations in TRPV4. This family comprises, in order of increasing severity, dominant brachyolmia, spondylo-metaphyseal dysplasia Kozlowski type, and metatropic dysplasia.Wetested the hypothesis that a further condition, Spondylo-epiphyseal dysplasia (SED), Maroteaux type (MIM 184095; also known as pseudo-Morquio syndrome type 2), could be caused by TRPV4 mutations. We analyzed six individuals with Maroteaux type SED, including three who had previously been reported. All six patients were found to have heterozygous TRPV4 mutations; three patients had unreported mutations, while three patients had mutations previously described in association with metatropic dysplasia. In addition, we tested one individual with a distinct rare disorder, parastremmatic dysplasia (MIM 168400). This patient had a common, recurrent mutation seen in several patients with Kozlowski type spondylo-metaphyseal dysplasia. We conclude that SED Maroteaux type and parastremmatic dysplasia are part of the TRPV4 dysplasia family and that TRPV4 mutations show considerable variability in phenotypic expression resulting in distinct clinical radiographic phenotypes. © 2010 Wiley-Liss, Inc.


PubMed | Clinical Genetic Unit and Royal Medical Services
Type: | Journal: Clinical medicine insights. Pediatrics | Year: 2015

Cyclopia (alobar holoprosencephaly) (OMIM% 236100) is a rare and lethal complex human malformation, resulting from incomplete cleavage of prosencephalon into right and left hemispheres occurring between the 18th and the 28th day of gestation. Holoprosencephaly occurs in 1/16,000 live births, and 1/250 during embryogenesis. Approximately 1.05 in 100,000 births are identified as infants with cyclopia, including stillbirths. Cyclopia typically presents with a median single eye or a partially divided eye in a single orbit, absent nose, and a proboscis above the eye. Extracranial malformations described in stillbirths with cyclopia include polydactyl, renal dysplasia, and an omphalocele. The etiology of this rare syndrome, which is incompatible with life, is still largely unknown. Most cases are sporadic. Heterogeneous risk factors have been implicated as possible causes.A live full-term baby with birth weight of 2900 g, product of cesarean section because of severe fetal bradycardia, was born at Prince Hashem Military Hospital - Zarqa city/Jordan. This newborn was the first baby to a non-consanguineous family, and a healthy 18-year-old mother, with no history of drug ingestion or febrile illnesses during pregnancy. Antenatal history revealed severe hydrocephalus diagnosed early by intrauterine ultrasound but the pregnancy was not terminated because of the lack of medical legitimization in the country. On examination, the newborn was found to have a dysmorphic face, with a median single eye, absence of nose, micrognathia, and a proboscis above the eye, all of which made cyclopia the possible initial diagnosis. Multiple unusual abdominal defects were present that include a huge omphalocele containing whole liver and spleen, urinary bladder extrophy, and undefined abnormal external genitalia, which called for urgent confirmation. Brain MRI was done and revealed findings consistent with alobar holoprosencephaly (cyclopia).Presentation of cyclopia is not fully exposed and new cyclopian syndromes still can appear. The prenatal diagnosis of cyclopia can be made early by ultrasound, and the awareness of the spectrum of sonographic findings of cyclopia can improve the accuracy of prenatal diagnosis. The legitimization of pregnancy termination for indexed cases in many countries around the world should be revised.

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