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1.
J Med Internet Res ; 22(10): e19263, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33090109

RESUMO

BACKGROUND: Collectively, an estimated 5% of the population have a genetic disease. Many of them feature characteristics that can be detected by facial phenotyping. Face2Gene CLINIC is an online app for facial phenotyping of patients with genetic syndromes. DeepGestalt, the neural network driving Face2Gene, automatically prioritizes syndrome suggestions based on ordinary patient photographs, potentially improving the diagnostic process. Hitherto, studies on DeepGestalt's quality highlighted its sensitivity in syndromic patients. However, determining the accuracy of a diagnostic methodology also requires testing of negative controls. OBJECTIVE: The aim of this study was to evaluate DeepGestalt's accuracy with photos of individuals with and without a genetic syndrome. Moreover, we aimed to propose a machine learning-based framework for the automated differentiation of DeepGestalt's output on such images. METHODS: Frontal facial images of individuals with a diagnosis of a genetic syndrome (established clinically or molecularly) from a convenience sample were reanalyzed. Each photo was matched by age, sex, and ethnicity to a picture featuring an individual without a genetic syndrome. Absence of a facial gestalt suggestive of a genetic syndrome was determined by physicians working in medical genetics. Photos were selected from online reports or were taken by us for the purpose of this study. Facial phenotype was analyzed by DeepGestalt version 19.1.7, accessed via Face2Gene CLINIC. Furthermore, we designed linear support vector machines (SVMs) using Python 3.7 to automatically differentiate between the 2 classes of photographs based on DeepGestalt's result lists. RESULTS: We included photos of 323 patients diagnosed with 17 different genetic syndromes and matched those with an equal number of facial images without a genetic syndrome, analyzing a total of 646 pictures. We confirm DeepGestalt's high sensitivity (top 10 sensitivity: 295/323, 91%). DeepGestalt's syndrome suggestions in individuals without a craniofacially dysmorphic syndrome followed a nonrandom distribution. A total of 17 syndromes appeared in the top 30 suggestions of more than 50% of nondysmorphic images. DeepGestalt's top scores differed between the syndromic and control images (area under the receiver operating characteristic [AUROC] curve 0.72, 95% CI 0.68-0.76; P<.001). A linear SVM running on DeepGestalt's result vectors showed stronger differences (AUROC 0.89, 95% CI 0.87-0.92; P<.001). CONCLUSIONS: DeepGestalt fairly separates images of individuals with and without a genetic syndrome. This separation can be significantly improved by SVMs running on top of DeepGestalt, thus supporting the diagnostic process of patients with a genetic syndrome. Our findings facilitate the critical interpretation of DeepGestalt's results and may help enhance it and similar computer-aided facial phenotyping tools.

2.
Genet Med ; 22(11): 1863-1873, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32699352

RESUMO

PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

3.
Eur J Med Genet ; 63(9): 103973, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32505691

RESUMO

Cohen syndrome (CS) is a rare, autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial abnormalities, abnormal truncal fat distribution, myopia, and pigmentary retinopathy. It is often considered an underdiagnosed condition, especially in children with developmental delay and intellectual disability. Here we report on four individuals from a large Jordanian family clinically diagnosed with CS. Using Trio Exome Sequencing (Trio-WES) and MLPA analyses we identified a maternally inherited novel intronic nucleotide substitution c.3446-23T>G leading to the activation of a cryptic splice site and a paternally inherited multi-exon deletion in VPS13B (previously termed COH1) in the index patient. Expression analysis showed a strong decrease of VPS13B mRNA levels and direct sequencing of cDNA confirmed splicing at a cryptic upstream splice acceptor site, resulting in the inclusion of 22 intronic bases. This extension results in a frameshift and a premature stop of translation (p.Gly1149Valfs*9). Segregation analysis revealed that three affected maternal cousins were homozygous for the intronic splice site variant. Our data show causality of both alterations and strongly suggest the expansion of the diagnostic strategy to search for intronic splice variants in molecularly unconfirmed patients affected by CS.

4.
J Clin Ultrasound ; 48(4): 240-243, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31994200

RESUMO

We report the case of a fetus with sonographic characteristics of Beckwith-Wiedemann syndrome (BWS). A 30-year-old gravida 2 para 1 was referred to our fetal medicine unit with an omphalocele. Fetal macrosomia, organomegaly, and polyhydramnios but no macroglossia were detected and BWS was suspected. Genetic testing for BWS did not confirm the suspected diagnosis as the karyotype was normal. Symptomatic polyhydramnios led to repeated amnioreductions. At 35 + 5 weeks of gestation, a female neonate of 3660 g was delivered with APGAR scores of 6/7/8, after 1/5/10 min, respectively. The abnormal shape of the thorax, facial dysmorphism, need for ventilation, and generalized muscular hypotonia led to the suspicion of Kagami-Ogata syndrome (KOS), which was confirmed by genetic testing. KOS in our patient was caused by a large deletion in the MEG3-region on chromosome 14q32 affecting the maternal allele. In this report, we highlight the notion that when sonographic signs suggestive of BWS such as macrosomia, polyhydramnios, and omphalocele are present and genetic testing does not confirm the suspected diagnosis, KOS should be tested for.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico por imagem , Transtornos Cromossômicos/diagnóstico por imagem , Anormalidades Craniofaciais/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Hérnia Umbilical/diagnóstico por imagem , Poli-Hidrâmnios/diagnóstico por imagem , Dissomia Uniparental/patologia , Adulto , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Feminino , Idade Gestacional , Hérnia Umbilical/genética , Humanos , Recém-Nascido , Poli-Hidrâmnios/genética , Gravidez , Ultrassonografia Pré-Natal , Dissomia Uniparental/genética
5.
Brain ; 143(1): 55-68, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834374

RESUMO

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

6.
Int J Cancer ; 146(4): 999-1009, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31081934

RESUMO

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Predisposição Genética para Doença , Adulto , Fatores Etários , Neoplasias da Mama/genética , Monitoramento Epidemiológico , Feminino , Seguimentos , Alemanha/epidemiologia , Heterozigoto , Humanos , Incidência , Anamnese , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Medição de Risco , Fatores de Risco
7.
Am J Hum Genet ; 105(2): 395-402, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353022

RESUMO

The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.


Assuntos
Aciltransferases/genética , Encefalopatias/etiologia , Epilepsia/etiologia , Glicosilfosfatidilinositóis/biossíntese , Glicosilfosfatidilinositóis/deficiência , Deficiência Intelectual/etiologia , Mutação , Convulsões/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Encefalopatias/patologia , Criança , Pré-Escolar , Epilepsia/patologia , Feminino , Glicosilfosfatidilinositóis/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Masculino , Linhagem , Convulsões/genética , Homologia de Sequência , Adulto Jovem
8.
Am J Hum Genet ; 105(3): 631-639, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31353024

RESUMO

Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Haploinsuficiência , Proteínas de Membrana/genética , Transtornos do Neurodesenvolvimento/genética , Estudos de Coortes , Feminino , Humanos , Ligantes , Masculino , Linhagem , Sequenciamento Completo do Exoma
9.
Eur J Hum Genet ; 27(12): 1827-1835, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31320746

RESUMO

Variants in DONSON were recently identified as the cause of microcephaly, short stature, and limb abnormalities syndrome (MISSLA). The clinical spectra of MISSLA and Fanconi anaemia (FA) strongly overlap. For that reason, some MISSLA patients have been clinically diagnosed with FA. Here, we present the clinical data of siblings with MISSLA featuring a novel DONSON variant and summarize the current literature on MISSLA. Additionally, we perform computer-aided image analysis using the DeepGestalt technology to test how distinct the facial features of MISSLA and FA patients are. We show that MISSLA has a specific facial gestalt. Notably, we find that also FA patients feature facial characteristics recognizable by computer-aided image analysis. We conclude that computer-assisted image analysis improves diagnostic precision in both MISSLA and FA.

10.
Cytogenet Genome Res ; 158(3): 126-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31203270

RESUMO

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.


Assuntos
Artrite Juvenil/diagnóstico , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico por imagem , Osteoartropatia Hipertrófica Primária/genética , Artrite Juvenil/genética , Diagnóstico Diferencial , Humanos , Masculino , Osteoartropatia Hipertrófica Primária/diagnóstico , Adulto Jovem
11.
Hum Genet ; 138(6): 593-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982135

RESUMO

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.


Assuntos
Dedos/anormalidades , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Polidactilia/genética , Dedos do Pé/anormalidades , Animais , Consanguinidade , Saúde da Família , Feminino , Dedos/patologia , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polidactilia/patologia , Dedos do Pé/patologia , Sequenciamento Completo do Exoma/métodos
12.
J Hum Genet ; 64(7): 609-616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31015584

RESUMO

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.


Assuntos
Transtornos do Crescimento/diagnóstico , Proteínas de Neoplasias/genética , Doenças do Nervo Óptico/diagnóstico , Anomalia de Pelger-Huët/diagnóstico , Agamaglobulinemia/sangue , Agamaglobulinemia/fisiopatologia , Cútis Laxa/diagnóstico , Cútis Laxa/genética , Cútis Laxa/patologia , Diagnóstico Diferencial , Tecido Elástico/ultraestrutura , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Humanos , Lactente , Fígado/enzimologia , Fígado/patologia , Masculino , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Anomalia de Pelger-Huët/genética , Anomalia de Pelger-Huët/patologia , Progéria/diagnóstico , Progéria/genética , Pele/patologia , Síndrome , Sequenciamento Completo do Exoma , Adulto Jovem
13.
Genet Med ; 21(10): 2216-2223, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30976099

RESUMO

PURPOSE: To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. METHODS: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT. RESULTS: All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. CONCLUSION: We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies-hypotonia-seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.


Assuntos
Aciltransferases/metabolismo , Glicosilfosfatidilinositóis/deficiência , Glicosilfosfatidilinositóis/metabolismo , Convulsões/metabolismo , Anormalidades Múltiplas/genética , Aciltransferases/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Feminino , Estudos de Associação Genética , Genótipo , Glicosilfosfatidilinositóis/genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Linhagem , Fenótipo , Convulsões/genética
15.
BMC Med Genomics ; 12(1): 6, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630535

RESUMO

BACKGROUND: Two interstitial microdeletions Xp11.22 including the CLCN5 and SHROOM4 genes were recently reported in a male individual affected with Dent disease, short stature, psychomotor delay and minor facial anomalies. Dent disease, characterized by a specific renal phenotype, is caused by truncating mutations of CLCN5 in the majority of affected cases. CASE PRESENTATION: Here, we present clinical and molecular findings in a male patient with clinical signs of Dent disease, developmental delay, short stature, microcephaly, and facial dysmorphism. Using molecular karyotyping we identified a hemizygous interstitial microdeletion Xp11.23p.11.22 of about 700 kb, which was inherited from his asymptomatic mother. Among the six deleted genes is CLCN5, which explains the renal phenotype in our patient. SHROOM4, which is partially deleted in this patient, is involved in neuronal development and was shown to be associated with X-linked intellectual disability. This is a candidate gene, the loss of which is thought to be associated with his further clinical manifestations. To rule out mutations in other genes related to intellectual disability, whole exome sequencing was performed. No other pathogenic variants that could explain the phenotypic features, were found. CONCLUSION: We compared the clinical findings of the patient presented here with the reported case with an Xp11.22 microdeletion including CLCN5 and SHROOM4 and re-defined the phenotypic spectrum associated with this microdeletion.


Assuntos
Canais de Cloreto/genética , Deleção Cromossômica , Proteínas do Citoesqueleto/genética , Doença de Dent/complicações , Doença de Dent/genética , Nanismo/complicações , Deficiência Intelectual/complicações , Microcefalia/complicações , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
16.
Genet Med ; 21(8): 1797-1807, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30679821

RESUMO

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.


Assuntos
Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Neurodesenvolvimento/genética , Comportamento Problema , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Proteínas de Ligação a DNA/genética , Genoma Humano/genética , Haploinsuficiência/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Proteínas Nucleares/genética , Fenótipo , Proteínas/genética , Sequenciamento Completo do Exoma
17.
Genet Med ; 21(6): 1295-1307, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Exoma , Face/anormalidades , Feminino , Estudos de Associação Genética/métodos , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Micrognatismo/genética , Pessoa de Meia-Idade , Mutação , Pescoço/anormalidades , Penetrância
19.
Nat Commun ; 9(1): 4250, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315159

RESUMO

Germline mutations in the ubiquitously expressed ACTB, which encodes ß-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we demonstrate cohort specific changes to ß-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs). These perturbed interactions are supported by in silico modeling and are validated in disease-relevant thrombocytes. Co-examination of actin and microtubule cytoskeleton constituents in patient-derived megakaryocytes and thrombocytes indicates that these ß-CYA mutations inhibit the final stages of platelet maturation by compromising microtubule organization. Our results define an ACTB-associated clinical syndrome with a distinct genotype-phenotype correlation and delineate molecular mechanisms underlying thrombocytopenia in this patient cohort.


Assuntos
Actinas/genética , Éxons/genética , Trombocitopenia/genética , Actinas/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Citoesqueleto/metabolismo , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Megacariócitos/metabolismo , Mutação/genética , Fenótipo , Trombocitopenia/metabolismo
20.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167850

RESUMO

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Assuntos
Proteínas de Transporte/genética , Canalopatias/genética , Deficiências do Desenvolvimento/genética , Marcadores Genéticos , Variação Genética , Proteínas de Membrana/genética , Canais de Sódio/genética , Adolescente , Adulto , Canalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
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