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1.
Mol Genet Genomic Med ; : e939, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454185

RESUMO

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. METHODS: Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. RESULTS: Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. CONCLUSION: Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.

2.
Eur J Med Genet ; : 103726, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319223

RESUMO

GRM1 gene, that is located on 6q24.3, encodes the metabotropic glutamate receptor type 1 (mGluR1), a transmembrane protein highly expressed in cerebellar Purkinje cells. Pathogenic variants in GRM1 have been reported only three times in humans, causing autosomal-recessive cerebellar ataxia with early-onset and intellectual disability or dominant forms of cerebellar ataxia with less severe phenotype in adults. We report a six-year-old boy, born to inbred parents, with an early-onset cerebellar syndrome due to a homozygous autosomal-recessive GRM1 pathogenic variant. In addition to cerebellar ataxia, axial hypotonia and oculomotor signs, he showed a severe and global developmental delay with lack of walking and speech and slight facial dysmorphic features. Brain MRI, performed at 1 year and at 5 years, showed a slowly progressive cerebellar atrophy. A novel homozygous truncating variant in the second exon of GRM1 gene (c.889C>T, p.(Arg297*)), inherited from the heterozygous healthy parents, was found by exome sequencing. Our observation not only emphasizes the central role of mGluR1-mediated signaling in cerebellar function and neurodevelopment but also provides valuable insights into the early clinical signs of recessive ataxia due to GRM1 pathogenic variants that were not reported previously. The difficulties of clinical differential diagnosis between this disease and other forms of congenital ataxia and the unspecific cerebellar atrophy on MRI highlight the importance of large-scale genetic investigations.

3.
Hum Mutat ; 2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31230393

RESUMO

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

4.
Orphanet J Rare Dis ; 14(1): 121, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151468

RESUMO

Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as "overfriendliness" and "hyersociability". WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic.Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin.The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in "typical" WBS patients: therefore, the terms "overfriendliness" and "hypersociability" appear to be a misleading oversimplification.The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.

5.
Cytogenet Genome Res ; 157(3): 141-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947196

RESUMO

Chromosomal microarray (CMA) is currently considered as a first-tier test in the genetic assessment of patients presenting with intellectual disability and/or multiple congenital abnormalities. The distinction between pathogenic CNVs, polymorphisms, and variants of unknown significance can be a diagnostic dilemma for cytogeneticists. The size of the CNV has been proposed as a useful criterion. We herein report the characterization of a 13.6-Mb interstitial duplication 20p11.1p12.1, found in a child presenting with mild global developmental delay, by standard karyotype and CMA. Unexpectedly, the same CNV was detected in the patient's mother and pregnant sister, who were healthy. On the basis of these results, an implication of this CNV in the neurological problems observed in the proband was considered to be unlikely. This report underlines the complexity of genetic counseling concerning rare chromosomal abnormalities, when little information is available either in the literature or in international cytogenetic databases.


Assuntos
Duplicação Cromossômica , Coloração Cromossômica/métodos , Anormalidades Congênitas/genética , Deficiência Intelectual/genética , Criança , Variações do Número de Cópias de DNA , Feminino , Aconselhamento Genético , Humanos , Masculino , Mães , Linhagem , Irmãos
6.
J Thromb Haemost ; 17(7): 1097-1103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31021037

RESUMO

Essentials No F8 genetic abnormality is detected in about 2% of severe hemophilia A patients. Detection of F8 structural variants remains a challenge. We identified a new F8 rearrangement in a severe hemophilia A patient using nanopore sequencing. We highlight the value of single-molecule long-read sequencing technologies in a genomics laboratory. BACKGROUND: No F8 genetic abnormality is detected in about 2% of severe hemophilia A patients using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal. OBJECTIVE: To characterize, in a genetically unresolved severe hemophilia A patient, a new Xq28 rearrangement disrupting F8 using comprehensive molecular techniques including nanopore sequencing. RESULTS: Long-range polymerase chain reaction (PCR) performed throughout F8 identified a nonamplifiable region in intron 25 indicating the presence of a genomic rearrangement. F8 messanger ribonucleic acid (mRNA) analysis including 3'rapid amplification of complementary deoxyribonucleic acid (cDNA) ends and nanopore sequencing found the presence of a F8 fusion transcript in which F8 exon 26 was replaced by a 742-bp pseudoexon corresponding to a noncoding region located at the beginning of the long arm of chromosome X (Xq12; chrX: 66 310 352-66 311 093, GRCh37/hg19). Cytogenetic microarray analysis found the presence of a Xq11.1q12 gain of 3.8 Mb. The PCR amplification of junction fragments and fluorescent in situ hybridization (FISH) analysis found that the Xq11q12 duplicated region was inserted in the F8 intron 25 genomic region. CONCLUSION: We characterized a novel genomic rearrangement in which a 3.8-Mb Xq11.1q12 gain inserted in the F8 intron 25 led to an aberrant fusion transcript in a patient with severe hemophilia A (HA), using comprehensive molecular techniques. This study highlights the value of single-molecule long-read sequencing technologies for molecular diagnosis of HA especially when conventional genetic approaches have failed.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30126759

RESUMO

Christianson syndrome (CS) is a X-linked neurodevelopmental disorder, including severe intellectual disability (ID), progressive microcephaly, ataxia, autistic behaviour (ASD), near absent speech, and epilepsy. Electrical status epilepticus in sleep (ESES) has been reported in two patients. We describe five male patients from three unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy-number variation involving SLC9A6. ESES was present in three out of the five patients in the critical age window between 4 and 8 years. All patients presented with severe intellectual disability, autistic features, and hyperactivity. Epilepsy onset occurred within the first two years of life. Seizures were of various types. In the two boys with a 20-years follow-up, epilepsy was drug-resistant during childhood, and became less active in early adolescence. Psychomotor regression was noted in two patients presenting with ESES. It was difficult to assess to what extent ESES could have contributed to the pathophysiological process, leading to regression of the already very limited communication skills. The two published case reports and our observation suggests that ESES could be a constitutive feature of Christianson syndrome, as it has already been shown for other Mendelian epileptic disorders, such as GRIN2A and CNKSR2-related developmental epileptic encephalopathies. Sleep EEG should be performed in patients with Christianson syndrome between 4 and 8 years of age. ESES occurring in the context of ID, ASD and severe speech delay, could be helpful to make a diagnosis of CS.

8.
Epileptic Disord ; 20(4): 289-294, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078772

RESUMO

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Encefalopatias , Epilepsia , Hiperecplexia , Doenças do Recém-Nascido , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Tremor , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/fisiopatologia , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Hiperecplexia/diagnóstico , Hiperecplexia/genética , Hiperecplexia/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Masculino , Tremor/diagnóstico , Tremor/genética , Tremor/fisiopatologia
10.
Clin Case Rep ; 6(5): 827-834, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29744066

RESUMO

Chromosomal microarray (CMA) can detect pathogenic copy number variations in 15-20% of individuals with intellectual disability and in 10% of patients with autism spectrum disorders. The diagnostic rate in specific learning disorders (SLD) is unknown. Our study emphasizes the usefulness of CMA in the diagnostic workout assessment of familial SLD.

11.
Ann Neurol ; 83(5): 926-934, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29630738

RESUMO

OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.

12.
Mol Syndromol ; 8(6): 325-330, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29230163

RESUMO

We report a 3-generation family in which 2 Xp copy number variations (CNVs) co-segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postnatally, her child, the proband's nephew, presented with autism spectrum disorders. aCGH revealed a 339-kb IL1RAPL1 duplication. Overall, the proband, his mother, and one of his sisters all harboured both CNVs, while his other sister and the 2 sons of each sister only carried the IL1RAPL1 intragenic duplication. As seen in this family, we emphasise the importance of small CNV detection, the pathogenicity of IL1RAPL1 exonic duplications in male carriers, and the difficulties for genetic counselling with the risk of double diagnosis in a single patient.

13.
Am J Med Genet A ; 173(8): 2268-2274, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28599093

RESUMO

We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1. Here, we report three further patients carrying proximal 2p14 microdeletions not including OTX1 and one patient carrying a more distal 2p14p15 microdeletion including this gene, providing new insights into the associated phenotypic spectrum. First, our study and a review of the literature showed that 3/4 patients carrying proximal 2p14 microdeletions had sensorineural hearing loss, suggesting the presence of a previously unreported deafness-causing gene in this chromosomal region. Second, one patient developed a progressive cardiomyopathy, suggesting that a cardiac follow-up should be systematically warranted even in the absence of congenital heart disease. We speculate that ACTR2 and MEIS1 might respectively play a role in the pathogenesis of the observed deafness and cardiomyopathy. Third, we observed other previously unreported features such as glaucoma, retinopathy, and mild midline abnormalities including short corpus callosum, hypospadias and anteriorly placed anus. Finally, the patient carrying a 2p14p15 deletion including OTX1 had normal kidneys and genitalia, thus confirming that OTX1 haploinsufficiency is not invariably associated with genitourinary defects. In conclusion, our study contributes significantly to delineate the phenotypic spectrum of 2p14 microdeletions.


Assuntos
Proteína 2 Relacionada a Actina/genética , Deficiência Intelectual/genética , Proteína Meis1/genética , Fatores de Transcrição Otx/genética , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , França , Haploinsuficiência/genética , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Espanha
14.
J Pediatr Genet ; 6(2): 84-91, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28496995

RESUMO

Whole genome array technology is an essential tool for the detection of a large number of copy number variants (CNVs) in patients with ID and/or multiple congenital anomalies. However, the clinical significance of some microimbalances is not known. In this article, we succeeded to detect seven new variations of unknown significance (dup12p13.33, dup2p16.3, dupXq13.2, del12q24.33, dup16p13.11, trip4q22.1, and dup9p21.3), one CNV classified as known pathogenic syndrome (del22q13.31-q33), and one CNV classified as potentially pathogenic (del11q24.3). We emphasize the role of comparative genomic hybridization arrays in the investigation of intellectual disability and evaluate the usefulness of existing systems in the interpretation of CNVs.

15.
Am J Med Genet A ; 173(3): 654-660, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28160395

RESUMO

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/genética , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Fenótipo , Testículo/anormalidades , Encéfalo/patologia , Pré-Escolar , Facies , Evolução Fatal , Doenças dos Genitais Masculinos/patologia , Hormônios Esteroides Gonadais/sangue , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Pênis/anormalidades , Pênis/patologia , Irmãos , Síndrome
16.
Eur J Hum Genet ; 25(3): 376-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28051072

RESUMO

We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G>C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Consanguinidade , Feminino , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Irmãos , Síndrome
17.
Eur J Hum Genet ; 24(12): 1761-1770, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27352968

RESUMO

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORß), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adulto , Criança , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Códon sem Sentido , Deficiências do Desenvolvimento/diagnóstico , Epilepsia Generalizada/diagnóstico , Exoma , Éxons , Feminino , Humanos , Masculino , Linhagem , Síndrome , Translocação Genética
18.
Eur J Hum Genet ; 24(7): 1001-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26486472

RESUMO

West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.


Assuntos
GTP Fosfo-Hidrolases/genética , Homozigoto , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto , Fator G para Elongação de Peptídeos/genética , Espasmos Infantis/genética , Sítios de Ligação , Sequência Conservada , Exoma , Feminino , GTP Fosfo-Hidrolases/metabolismo , Teste de Complementação Genética , Humanos , Lactente , Masculino , Proteínas Mitocondriais/metabolismo , Linhagem , Fator 1 de Elongação de Peptídeos , Fator G para Elongação de Peptídeos/metabolismo , Ligação Proteica , Espasmos Infantis/patologia , Leveduras/genética
19.
Cytogenet Genome Res ; 147(2-3): 111-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26669311

RESUMO

Supernumerary ring chromosomes (SRC) are usually derived from regions adjacent to the centromere. Their identification may be challenging, particularly in case of low mosaicism. Here, we report on a patient who was referred for major in utero growth retardation, severe developmental delay, facial dysmorphism, cleft palate, and hypospadias. The karyotype showed a small SRC in mosaic. The combination of FISH, M-FISH and array-CGH was necessary for a complete characterization of this SRC. M-FISH revealed that the SRC originated from chromosome 7. Array-CGH performed with a 400K oligonucleotide array showed a gain in region 7q22.1q31.1 present in low mosaic. This result was confirmed by FISH using BAC probes specific for chromosome 7. The SRC was a neocentric ring derived from 7q22.1q31.1 and was found in only 8% of the cells. This is the first patient carrying a mosaic neocentric SRC derived from the long arm of chromosome 7. Our study emphasizes the need to combine different techniques and to use adapted bioinformatic tools for low-mosaicism marker identification. It also contributes to the delineation of the partial trisomy 7q phenotype.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7/genética , Mosaicismo , Cromossomos em Anel , Centrômero/genética , Criança , Pré-Escolar , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento , Face/anormalidades , Retardo do Crescimento Fetal , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariotipagem , Masculino
20.
J Clin Invest ; 125(3): 1124-8, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25642776

RESUMO

Idiopathic scoliosis (IS) is a spine deformity that affects approximately 3% of the population. The underlying causes of IS are not well understood, although there is clear evidence that there is a genetic component to the disease. Genetic mapping studies suggest high genetic heterogeneity, but no IS disease-causing gene has yet been identified. Here, genetic linkage analyses combined with exome sequencing identified a rare missense variant (p.A446T) in the centriolar protein gene POC5 that cosegregated with the disease in a large family with multiple members affected with IS. Subsequently, the p.A446T variant was found in an additional set of families with IS and in an additional 3 cases of IS. Moreover, POC5 variant p.A455P was present and linked to IS in one family and another rare POC5 variant (p.A429V) was identified in an additional 5 cases of IS. In a zebrafish model, expression of any of the 3 human IS-associated POC5 variant mRNAs resulted in spine deformity, without affecting other skeletal structures. Together, these findings indicate that mutations in the POC5 gene contribute to the occurrence of IS.


Assuntos
Proteínas de Transporte/genética , Escoliose/genética , Animais , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único , Peixe-Zebra
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