RESUMO
Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
Assuntos
Proteína 7 com Repetições F-Box-WD , Transtornos do Neurodesenvolvimento , Ubiquitinação , Proteína 7 com Repetições F-Box-WD/química , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Transtornos do Neurodesenvolvimento/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: To date, almost no research on the psychosocial implications of albinism has been conducted in France and an exploration of albinism-related experiences could be beneficial, in order to better understand this condition. The aim of this study was to examine how French people with albinism and their parents live with and adapt to this condition in all the areas of their lives. METHODS: Semi-structured phone interviews were conducted with 9 parent-child dyads, each participating separately. Participants were recruited by convenience sampling, thanks to the combined efforts of a patient association (Genespoir) and professionals from the partner medical referral centers involved in the project. Dyads in which the individual with albinism had any comorbidity were excluded. The interviews were then transcribed and subjected to in-depth thematic analysis. Two codebooks were constructed in a mirrored process: one for people with albinism; the other for their parents. They were finally merged at the end of the coding step. RESULTS: Four main categories were identified: personal perceptions and social representations of albinism, difficulties and obstacles encountered by people with albinism, resources and facilitators, and the importance of parent-child functioning. The results indicated that experiences of stigmatization during childhood and adolescence are common and that people with albinism face challenges in adapting to certain obstacles related to their visual impairments (VI) (e.g., inability to drive a car; eye strain...). Parents emerged as one, if not as the main, source of support for people with albinism throughout their development. Although external support systems exist to assist them in various aspects of their lives, some of them primarily rely on their own personal resources to cope. CONCLUSIONS: This research highlights the importance of a systemic and transdisciplinary approach to make sure families receive the support that best meets their needs.
Assuntos
Albinismo , População Europeia , Apoio Familiar , Pais , Adolescente , Adulto , Humanos , Albinismo/epidemiologia , Albinismo/psicologia , População Europeia/psicologia , França , Pais/psicologia , Pesquisa Qualitativa , Estigma Social , Apoio SocialRESUMO
BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.
Assuntos
Síndrome de Costello , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Síndrome de Costello/genética , Síndrome de Costello/complicações , Estudos Prospectivos , Feminino , Masculino , Criança , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Pré-Escolar , Adulto , Adulto Jovem , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Síndrome de Noonan/complicações , Acantose Nigricans/genética , Diagnóstico Diferencial , Ceratodermia Palmar e Plantar/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/complicações , Fenótipo , Papiloma/genética , Papiloma/patologia , Acitretina/uso terapêutico , Sobrancelhas/anormalidades , Sobrancelhas/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/etiologia , Lactente , Ceratolíticos/uso terapêutico , FáciesRESUMO
The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.
Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Mutação , Detecção Precoce de Câncer , Transtornos do Crescimento/diagnóstico , Tumor de Wilms/diagnóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
Ultraviolet B (UVB) in sunlight cause skin damage, ranging from wrinkles to photoaging and skin cancer. UVB can affect genomic DNA by creating cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidine (6-4) photoproducts (6-4PPs). These lesions are mainly repaired by the nucleotide excision repair (NER) system and by photolyase enzymes that are activated by blue light. Our main goal was to validate the use of Xenopus laevis as an in vivo model system for investigating the impact of UVB on skin physiology. The mRNA expression levels of xpc and six other genes of the NER system and CPD/6-4PP photolyases were found at all stages of embryonic development and in all adult tissues tested. When examining Xenopus embryos at different time points after UVB irradiation, we observed a gradual decrease in CPD levels and an increased number of apoptotic cells, together with an epidermal thickening and an increased dendricity of melanocytes. We observed a quick removal of CPDs when embryos are exposed to blue light versus in the dark, confirming the efficient activation of photolyases. A decrease in the number of apoptotic cells and an accelerated return to normal proliferation rate was noted in blue light-exposed embryos compared with their control counterparts. Overall, a gradual decrease in CPD levels, detection of apoptotic cells, thickening of epidermis, and increased dendricity of melanocytes, emulate human skin responses to UVB and support Xenopus as an appropriate and alternative model for such studies.
Assuntos
Dano ao DNA , Desoxirribodipirimidina Fotoliase , Animais , Humanos , Xenopus laevis/metabolismo , Desoxirribodipirimidina Fotoliase/genética , Desoxirribodipirimidina Fotoliase/metabolismo , Dímeros de Pirimidina/genética , Dímeros de Pirimidina/metabolismo , Raios Ultravioleta/efeitos adversosRESUMO
Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.
Assuntos
Disceratose Congênita/patologia , Retardo do Crescimento Fetal/patologia , Deficiência Intelectual/patologia , Microcefalia/patologia , Mutação , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fibrose Pulmonar/patologia , RNA Ribossômico/biossíntese , Ribonucleoproteínas Nucleares Pequenas/deficiência , Ribonucleoproteínas Nucleares Pequenas/genética , Idoso , Sequência de Aminoácidos , Disceratose Congênita/etiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Recém-Nascido , Deficiência Intelectual/etiologia , Masculino , Microcefalia/etiologia , Pessoa de Meia-Idade , Proteínas Nucleares/química , Linhagem , Regiões Promotoras Genéticas , Fibrose Pulmonar/etiologia , Ribonucleoproteínas Nucleares Pequenas/química , Homologia de Sequência , Telomerase/genética , Transcrição GênicaRESUMO
Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of nonphysiological porphyrin isomer I metabolites. Clinical features are heterogeneous among patients with CEP but usually combine skin photosensitivity and chronic hemolytic anemia, the severity of which is related to porphyrin overload. Therapeutic options include symptomatic strategies only and are unsatisfactory. One promising approach to treating CEP is to reduce the erythroid production of porphyrins through substrate reduction therapy by inhibiting 5-aminolevulinate synthase 2 (ALAS2), the first and rate-limiting enzyme in the heme biosynthetic pathway. We efficiently reduced porphyrin accumulation after RNA interference-mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent posttranscriptional regulation of ALAS2, we evaluated whether iron chelation with deferiprone could decrease ALAS2 expression and subsequent porphyrin production in vitro and in vivo in a CEP murine model. Treatment with deferiprone of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a patient with CEP inhibited iron-dependent protein ALAS2 and iron-responsive element-binding protein 2 expression and reduced porphyrin production. Furthermore, porphyrin accumulation progressively decreased in red blood cells and urine, and skin photosensitivity in CEP mice treated with deferiprone (1 or 3 mg/mL in drinking water) for 26 weeks was reversed. Hemolysis and iron overload improved upon iron chelation with full correction of anemia in CEP mice treated at the highest dose of deferiprone. Our findings highlight, in both mouse and human models, the therapeutic potential of iron restriction to modulate the phenotype in CEP.
Assuntos
Anemia Hemolítica/tratamento farmacológico , Deferiprona/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Transtornos de Fotossensibilidade/tratamento farmacológico , Porfiria Eritropoética/tratamento farmacológico , 5-Aminolevulinato Sintetase/antagonistas & inibidores , 5-Aminolevulinato Sintetase/biossíntese , 5-Aminolevulinato Sintetase/genética , Adulto , Anemia Hemolítica/etiologia , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Eritroides/efeitos dos fármacos , Células Eritroides/metabolismo , Feminino , Técnicas de Introdução de Genes , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/etiologia , Leucemia Eritroblástica Aguda/patologia , Camundongos , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Células-Tronco de Sangue Periférico/metabolismo , Transtornos de Fotossensibilidade/etiologia , Porfiria Aguda Intermitente/metabolismo , Porfiria Eritropoética/complicações , Porfirinas/biossíntese , Interferência de RNA , RNA Interferente Pequeno/farmacologiaRESUMO
Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Ensaios Clínicos como Assunto , Megalencefalia/diagnóstico por imagem , Megalencefalia/fisiopatologia , Neuroimagem , Dermatopatias Vasculares/diagnóstico por imagem , Dermatopatias Vasculares/fisiopatologia , Telangiectasia/congênito , Anormalidades Múltiplas/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Feminino , Previsões , Humanos , Imageamento por Ressonância Magnética , Masculino , Megalencefalia/tratamento farmacológico , Dermatopatias Vasculares/tratamento farmacológico , Telangiectasia/diagnóstico por imagem , Telangiectasia/tratamento farmacológico , Telangiectasia/fisiopatologia , Adulto JovemRESUMO
Hermansky-Pudlak syndrome (HPS) is a rare form of syndromic oculocutaneous albinism caused by disorders in lysosome-related organelles. Ten genes are associated with different forms of HPS. HPS type 9 (HPS-9) is caused by biallelic variants of BLOC1S6. To date, only three patients with HPS-9 have been reported. We described one patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. By reviewing the previous published cases we confirm the phenotype of HPS-9 patients. This patient is the only one described with dextrocardia and abnormal psychomotor development.
Assuntos
Albinismo/sangue , Plaquetas/metabolismo , Síndrome de Hermanski-Pudlak/sangue , Feminino , Humanos , LactenteRESUMO
PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
Assuntos
Anormalidades Craniofaciais/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Síndrome de Marfan/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Fatores de Transcrição NFI/genética , Adolescente , Adulto , Criança , Montagem e Desmontagem da Cromatina , Anormalidades Craniofaciais/patologia , Exoma/genética , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/patologia , Masculino , Síndrome de Marfan/patologia , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.
Assuntos
Feto/anormalidades , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise Citogenética , Família , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação/genética , LinhagemRESUMO
Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
Assuntos
Aracnodactilia/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Loeys-Dietz/genética , Fator de Crescimento Transformador beta3/genética , Adolescente , Adulto , Aracnodactilia/patologia , Criança , Pré-Escolar , Doenças do Tecido Conjuntivo/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Homozigoto , Humanos , Síndrome de Loeys-Dietz/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Fator de Crescimento Transformador beta3/deficiência , Adulto JovemRESUMO
Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.
Assuntos
Cútis Laxa/fisiopatologia , Aldeído Desidrogenase/genética , Consanguinidade , Cútis Laxa/classificação , Cútis Laxa/genética , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.
Assuntos
Aberrações Cromossômicas , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Rearranjo Gênico , Estudos de Associação Genética , Fenótipo , Sequenciamento Completo do Genoma , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Masculino , Relação Estrutura-Atividade , Translocação Genética , Adulto JovemRESUMO
BACKGROUND: The diagnosis of PTEN hamartoma tumor syndrome (PHTS) is difficult in children because they usually do not meet diagnostic criteria. The objective of our study was to characterize lipoma as an early presentation of PHTS. METHODS: We performed a retrospective review of children with PHTS diagnosed in French academic hospitals from 2000 to 2019. We included patients presenting at least one lipoma and PTEN-related disorder confirmed genetically. RESULTS: Thirteen children were included (mean age 5.5 years [range 2.5-16]). All children had solitary (n = 5) or multiple (n = 8) lipomas, all located on the trunk. Clinical examination revealed macrocephaly in all patients. Genital lentiginosis was found in all patients in whom genitalia were examined (n = 6). CONCLUSIONS: In addition to the classical presentation of PHTS with neurological disorders and macrocephaly, some patients, especially the youngest ones, have an initial dermatologic presentation with multiple lipomas. Search for penile freckling and macrocephaly in these patients allows for the diagnosis of PHTS. Lipomatosis should be a major diagnostic criterion in children.
Assuntos
Síndrome do Hamartoma Múltiplo , Lipoma , Lipomatose , Megalencefalia , Adolescente , Criança , Pré-Escolar , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Humanos , Lipoma/diagnóstico , Lipoma/genética , Megalencefalia/diagnóstico , Megalencefalia/genética , PTEN Fosfo-Hidrolase/genética , Estudos RetrospectivosRESUMO
PUM1 has been very recently reported as responsible for a new form of developmental disorder named PADDAS syndrome. We describe here an additional patient with early onset developmental delay, epilepsy, microcephaly, and hair dysplasia, with a de novo heterozygous missense variant of PUM1: c.3439C > T, p.(Arg1147Trp). This variant was absent from databases and predicted deleterious by multiple softwares. The same missense variant has been reported by Gennarino et al., in a girl with much more severe epilepsy. Our report is in favor of a variable expressivity of PADDAS syndrome, and broadens the phenotypic spectrum with the description of hair dysplasia.
Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Fenótipo , Proteínas de Ligação a RNA/genética , Adolescente , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Hipotricose/diagnóstico , Hipotricose/genética , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , SíndromeAssuntos
Classe Ia de Fosfatidilinositol 3-Quinase , Fenótipo , Humanos , Feminino , Masculino , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinases/genética , Criança , Adolescente , Síndrome , Pré-Escolar , Adulto , Malformações Vasculares/genética , Malformações Vasculares/patologia , Malformações Vasculares/diagnóstico , Mutação , LactenteRESUMO
We report a 6-month-old girl born with a fronto-parietal patch of hair straighter than the remainder of the scalp hairs. We took a biopsy to rule out a congenital melanocytic nevus. We concluded after additional scanning electron microscopy study of the hair shafts that the lesion corresponds to a possible local mosaicism causing an isolated straight hair nevus phenotype.
Assuntos
Doenças do Cabelo/diagnóstico , Cabelo/patologia , Nevo Pigmentado/diagnóstico , Feminino , Doenças do Cabelo/patologia , Humanos , Lactente , Microscopia Eletrônica de Varredura , MosaicismoRESUMO
The focal facial dermal dysplasias (FFDDs) are a group of rare inherited developmental disorders characterized by congenital scar-like atrophic lesions in the bitemporal (FFDD1, 2, and 3) or preauricular (FFDD4) areas. FFDD4 is an autosomal-recessive trait characterized by preauricular skin defects without additional dysmorphic findings. Previously, only two CYP26C1 mutations in four unrelated patients with FFDD4 were reported. Here, we report two additional unrelated FFDD4 patients with four CYP26C1 mutations including three novel lesions: a missense mutation, c.230G>C (p.Arg77Pro), and two splice-site mutations, c.1191+1G>T (IVS5(+1)G>T) and c.1191+2insT (IVS5(+2)insT). In silico analyses predicted all three mutations as pathogenic. Compound heterozygosity was validated through parental studies. These results provide further evidence that CYP26C1 mutations are the molecular genetic basis of FFDD4. Identification of additional cases by dermatologists, pediatricians, and medical geneticists will lead to further understanding of the clinical spectrum of FFDD4 and define its molecular genetic heterogeneity.