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1.
Am J Hum Genet ; 105(2): 403-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303265

RESUMO

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

2.
Neurogenetics ; 20(3): 145-154, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209758

RESUMO

Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible gene is EHMT1. A 9q34 duplication syndrome (9q34 DS) had been reported in literature, but it has never been characterized by a detailed molecular analysis of the gene content and endpoints. To the best of our knowledge, we report on the first patient carrying the smallest 9q34.3 duplication containing EHMT1 as the only relevant gene. We compared him with 21 reported patients described here as carrying 9q34.3 duplications encompassing the entire gene and extending within ~ 3 Mb. By surveying the available clinical and molecular cytogenetic data, we were able to discover that similar neurodevelopmental disorders (NDDs) were shared by patient carriers of even very differently sized duplications. Moreover, some facial features of the 9q34 DS were more represented than those of KS. However, an accurate in silico analysis of the genes mapped in all the duplications allowed us to support EHMT1 as being sufficient to cause a NDD phenotype. Wider patient cohorts are needed to ascertain whether the rearrangements have full causative role or simply confer the susceptibility to NDDs and possibly to identify the cognitive and behavioral profile associated with the increased dosage of EHMT1.

3.
Am J Med Genet A ; 179(8): 1570-1574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111652

RESUMO

"Apple peel" intestinal atresia is a rare form of small bowel atresia, in which the duodenum or proximal jejunum ends in a blind pouch and the distal small bowel wraps around its vascular supply, in a spiral resembling an apple peel. The etiology of "apple peel" intestinal atresia is presently unknown, although a congenital or acquired intestinal vascular accident can have a role in the pathogenesis. We report a family in which the proband affected by "apple peel" intestinal atresia, had a sibling (an interrupted pregnancy), and a paternal cousin with cardiac left-sided obstructive lesions. Molecular testing for NOTCH1 gene was carried out in the proband, because pathogenic mutations in this gene have been associated with familial and sporadic cardiac left-sided obstructive lesions and vascular anomalies, both isolated or within the spectrum of the Adams-Oliver syndrome (AOS). The heterozygous c.2734C>T (p.Arg912Trp) NOTCH1 variant was found in the proband with "apple peel" intestinal atresia and in his father. This result argues for a possible causal relationship between NOTCH1 gene mutations and some forms of intestinal defects, through a vascular mechanism. The spectrum of NOTCH1-associated malformations is widened. Genetic counseling should take into account intrafamilial variable clinical expression and incomplete penetrance.

4.
Hum Mutat ; 40(8): 1013-1029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31021519

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

5.
Am J Hum Genet ; 103(4): 621-630, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290154

RESUMO

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.

6.
Eur J Med Genet ; 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30189253

RESUMO

TARP syndrome (TARPS) is an X-linked syndromic condition including Robin sequence, congenital heart defects, developmental delay, feeding difficulties and talipes equinovarus, as major features. The disease is caused by inactivating mutations in RBM10 which encodes for a RNA binding motif protein involved in transcript processing. We herein report a male born from healthy and non-consanguineous parents, presenting prenatal record of intrauterine fetal growth retardation, and postnatal features including growth and developmental delays, CNS abnormalities, facial dysmorphisms, bilateral syndactyly at the hands, talipes equinovarus and congenital heart defects. By using trio-based Whole Exome Sequencing approach, a maternally inherited RBM10 frameshift variant causing decay of the RBM10 transcript was identified. Despite the syndrome is considered lethal in affected males, our subject with molecularly confirmed TARPS is still alive at 11 years of age supporting the chance of surviving. Long-term surviving in TARPS is extremely rare and should be considered in genetic counselling and clinical follow up of the syndrome. We provide the natural history of the syndrome, reviewing the major clinical characteristics. Congenital heart defects are confirmed as specific diagnostic markers for the syndrome. In addition, cardiac anatomical details are defining a possible clinical overlap with syndromic conditions related to the hedgehog pathway and/or primary cilium anomalies as Oral-Facial-Digital or Smith-Lemli-Opitz syndromes.

8.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

9.
Clin Genet ; 93(2): 401-407, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28374925

RESUMO

Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11-year-old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole-exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.

10.
Am J Med Genet A ; 173(11): 2912-2922, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28884922

RESUMO

The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%). Additional CHDs diagnosed in single patients included aortic dilatation with mitral anomaly and hypoplastic left heart syndrome. We also reviewed CHDs in patients with a molecular diagnosis of Kabuki syndrome reported in the literature. In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left-sided obstructive lesions, including multiple left-sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left-sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation.


Assuntos
Anormalidades Múltiplas/genética , Estenose da Valva Aórtica/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Cardiopatias Congênitas/genética , Doenças Hematológicas/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/fisiopatologia , Coartação Aórtica/complicações , Coartação Aórtica/genética , Coartação Aórtica/fisiopatologia , Valva Aórtica/anormalidades , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/fisiopatologia , Face/fisiopatologia , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Comunicação Interatrial/genética , Comunicação Interatrial/fisiopatologia , Comunicação Interventricular/genética , Comunicação Interventricular/fisiopatologia , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/fisiopatologia , Doenças Hematológicas/complicações , Doenças Hematológicas/fisiopatologia , Histona Desmetilases/genética , Humanos , Masculino , Proteínas Nucleares/genética , Doenças Vestibulares/complicações , Doenças Vestibulares/fisiopatologia
11.
Gene ; 628: 141-145, 2017 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698159

RESUMO

ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespie syndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia. We performed next generation sequencing in two simplex families with Gillespie syndrome and identified de novo pathological mutations localized in the C-terminal channel domain of ITPR1 in both patients: a recurrent deletion (p.Lys2596del) and a novel missense mutation (p.Asn2576Ile) close to a point of constriction in the Ca2+ pore. Our study expands the mutational spectrum of ITPR1 and confirms that ITPR1 screening should be implemented in patients with congenital cerebellar ataxia with or without iris hypoplasia.


Assuntos
Aniridia/genética , Ataxia Cerebelar/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Deficiência Intelectual/genética , Mutação , Adulto , Pré-Escolar , Análise Mutacional de DNA , Feminino , Deleção de Genes , Humanos , Mutação de Sentido Incorreto
12.
Am J Med Genet A ; 2017 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-28480548

RESUMO

Exome sequencing has led to the comprehension of the molecular bases of several forms of neurodevelopmental disorders, a clinically heterogeneous group of diseases characterized by intellectual disability (ID) and autism spectrum disorder (ASD). De novo mutations in POGZ has been causally linked to isolated ASD and syndromic ID, only recently. Here we report on a 15 year-old girl in whom exome sequencing allowed to identify a de novo POGZ truncating mutation as the molecular cause underlying a complex phenotype apparently not fitting any recognized syndrome. We describe the evolution of her clinical features with age, and review published clinical data of patients with POGZ mutations to systematically analyze the clinical spectrum associated with mutations. Our finding expands the clinical and molecular spectrum of POGZ mutations. Revision of the literature indicate that moderate to severe ID, microcephaly, variable CNS malformations, reduced growth, brachytelephalangy, and facial dysmorphism represent recurrent features associated with POGZ mutations.

13.
Am J Hum Genet ; 99(4): 962-973, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27666370

RESUMO

Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αß-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective ß-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble α/ß-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.


Assuntos
Alelos , Encefalopatias/genética , Proteínas Associadas aos Microtúbulos/genética , Microtúbulos/metabolismo , Mutação , Dobramento de Proteína , Tubulina (Proteína)/metabolismo , Adolescente , Idade de Início , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatias/patologia , Proliferação de Células , Pré-Escolar , Feminino , Fibroblastos , Humanos , Lactente , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/patologia , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Ligação Proteica , Fuso Acromático/metabolismo , Fuso Acromático/patologia , Tubulina (Proteína)/química
14.
Epileptic Disord ; 18(2): 123-36, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27267311

RESUMO

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Epilepsia/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Polegar/anormalidades , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/fisiopatologia , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Fibromatose Gengival/tratamento farmacológico , Fibromatose Gengival/fisiopatologia , Hallux/fisiopatologia , Deformidades Congênitas da Mão/tratamento farmacológico , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Masculino , Unhas Malformadas/tratamento farmacológico , Unhas Malformadas/fisiopatologia , Síndrome , Polegar/fisiopatologia , Adulto Jovem
15.
Am J Med Genet A ; 170(3): 661-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26686844

RESUMO

Sprengel anomaly (SA) is a rare skeletal defect characterized by uni- or bi-lateral elevation of the scapula. This anomaly is often isolated, although it can occur in association with other defects, including cervical spine malformations, cleft palate, and facial anomalies. Neural crest migration anomalies have been involved in the etiology of SA. Since the same embryological pathway accounts for some of the clinical features of deletion 22q11.2 syndrome (del22q11.2; DiGeorge/Velo-Cardio-Facial syndrome), we investigated the occurrence of SA in a consecutive series of 235 del22q11.2 patients aged more than 2 years, undergoing a complete clinical and orthopedic assessment of the dorsal and thoracic skeleton. In the present series, two patients were diagnosed with true SA. Present results and published reports suggest that scapular involvement including SA occurs in 1-2% of del22q11.2 individuals. Accordingly, this anomaly should be investigated as one of the possible skeletal findings of del22q11.2 syndrome, while this diagnosis should be excluded in patients presenting with SA associated with other defects.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Anormalidades Congênitas/diagnóstico , Síndrome de DiGeorge/diagnóstico , Escápula/anormalidades , Articulação do Ombro/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Escápula/diagnóstico por imagem , Escápula/metabolismo , Escápula/patologia , Articulação do Ombro/diagnóstico por imagem
16.
BMC Med Genet ; 16: 78, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26334530

RESUMO

BACKGROUND: CHARGE syndrome is an autosomal dominant disorder, characterized by ocular Coloboma, congenital Heart defects, choanal Atresia, Retardation, Genital anomalies and Ear anomalies. Over 90 % of typical CHARGE patients are mutated in the CHD7 gene, 65 %-70 % of the cases for all typical and suspected cases combined. The gene encoding for a protein involved in chromatin organization. The mutational spectrum include nonsense, frameshift, splice site, and missense mutations. Large deletions and genomic rearrangements are rare. CASE PRESENTATION: We report here on a 5.9 years old male of Moroccan origin displaying classic clinical features of CHARGE syndrome. Using CGH array and NGS analysis we detected a microdeletion (184 kb) involving the promoter region and exon 1 of CHD7 gene and the flanking RAB2 gene. CONCLUSION: The present observation suggests that deletion limited to the regulatory region of CHD7 is sufficient to cause the full blown CHARGE phenotype. Different size of deletions can result in different phenotypes, ranging from a milder to severe CHARGE syndrome; this is based on a combination of major and minor diagnostic characteristics, therefore to a more variable clinical features, likely due to the additive effect of other genetic imbalances. MLPA and CGH techniques should be considered in the diagnostic protocol of individuals with a clinical suspect of CHARGE syndrome.


Assuntos
Síndrome CHARGE/genética , Aberrações Cromossômicas , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Sequências Reguladoras de Ácido Nucleico/genética , Sequência de Bases , Síndrome CHARGE/patologia , Pré-Escolar , Hibridização Genômica Comparativa , Humanos , Masculino , Dados de Sequência Molecular , Marrocos , Análise de Sequência de DNA
18.
Nat Genet ; 47(6): 661-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25915598

RESUMO

Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Deformidades Congênitas da Mão/genética , ATPases Vacuolares Próton-Translocadoras/genética , Animais , Células CHO , Códon sem Sentido , Cricetinae , Cricetulus , Feminino , Estudos de Associação Genética , Humanos , Masculino , Potenciais da Membrana , Modelos Moleculares , Mutação de Sentido Incorreto , Linhagem , Conformação Proteica , Xenopus laevis
19.
Genome Res ; 25(2): 155-66, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25561519

RESUMO

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Mutação , RNA Polimerase III/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Transcrição Genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Encéfalo/patologia , Proliferação de Células , Criança , Pré-Escolar , Exoma , Facies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fenótipo , Conformação Proteica , Isoformas de Proteínas , Irmãos , Síndrome , Fatores Associados à Proteína de Ligação a TATA/química , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Peixe-Zebra
20.
Arch Dis Child ; 100(2): 158-64, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25281733

RESUMO

OBJECTIVE: To review the clinical and molecular genetic characteristics of 16 patients presenting a suspected diagnosis of Kabuki syndrome (KS) in the first year of life, to evaluate the clinical handles leading to a prompt diagnosis of KS in newborns. Clinical diagnosis of KS can be challenging during the first year of life, as many diagnostic features become evident only in subsequent years. METHODS: All patients were clinically investigated by trained clinical geneticists. A literature review was performed using the Pubmed online database and diagnostic criteria suggested by DYSCERNE-Kabuki Syndrome Guidelines (2010) were used (a European Network of Centres of Expertise for Dysmorphology, funded by the European Commission Executive Agency for Health and Consumers (DG Sanco), Project 2006122). Molecular analysis of the known causative genes of KS, KMT2D/MLL2 and KDM6A, was performed through MiSeq-targeted sequencing platform. All mutations identified were validated by Sanger sequencing protocols. RESULTS: Mutations in KMT2D gene were identified in 10/16 (62%) of the patients, whereas none of the patients had KDM6A mutations. Facial dysmorphisms (94%), feeding difficulties (100%) and hypotonia (100%) suggested the clinical diagnosis of KS. No significative differences in terms of facial features were noticed between mutation positive and negative patients of the cohort. Brachydactyly, joint laxity and nail dysplasia were present in about 80% of the patients. Other congenital anomalies were most commonly present in the mutated group of patients, including left-sided cardiac abnormalities, skeletal, renal and anorectal malformations and hypertricosis. CONCLUSIONS: We present an overview of patients with KS diagnosed during the first year of life. Early diagnosis is serviceable in terms of clinical management and for targeted genetic counselling.


Assuntos
Anormalidades Múltiplas/diagnóstico , Face/anormalidades , Doenças Hematológicas/diagnóstico , Doenças Vestibulares/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Feminino , Doenças Hematológicas/genética , Histona Desmetilases/genética , Humanos , Recém-Nascido , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Doenças Vestibulares/genética
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