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1.
Medicine (Baltimore) ; 99(45): e23033, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157955

RESUMO

INTRODUCTION: Microdeletion syndromes occur from deletion of 5Mb of a chromosome in approximately 5% of patients with unexplained intellectual disability. Interstitial microdeletions at bands 1p33 and 1p32.2 of the short arm of chromosome 1 are rare and have not been previously reported in relation to disease. PATIENT CONCERNS: We present a case of a 39-month boy with Pierre Robin sequence, development delay/intellectual disability, growth retardation, short stature, leukoencephalopathy, craniofacial dysplasia, and speech delay. The child was referred to the Child health care department in October 2014 for his delayed language development and aggravated aggression. DIAGNOSIS: Molecular diagnostic testing with G-band karyotyping was normal but clinical microarray analysis detected a 10 Mb microdeletion at 1p33p32.2. INTERVENTIONS: The patient received rehabilitation. OUTCOMES: Three candidate genes were pinpointed to the deleted area, including ORC1, SCP2, and DAB1. Phenotype-genotype analysis suggested that these three genes are likely to be responsible for the main phenotypes observed in the patient, such as microcephaly, growth retardation, short stature, leukoencephalopathy, and development delay/intellectual disability. CONCLUSIONS: The spectrum of phenotypes this case presented with are likely to be caused by 1p33p32.2 deletion which could represent a new microdeletion syndrome.


Assuntos
Cariotipagem/métodos , Análise em Microsséries/métodos , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Deleção Cromossômica , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Nanismo/diagnóstico , Nanismo/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Complexo de Reconhecimento de Origem/genética , Fenótipo , Síndrome de Pierre Robin/reabilitação
2.
BMC Med Genet ; 21(1): 192, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004012

RESUMO

BACKGROUND: Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. CASE PRESENTATION: A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. CONCLUSION: In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença/genética , Doenças Renais Císticas/genética , Mutação , Proteínas da Gravidez/genética , Retina/anormalidades , Fatores Supressores Imunológicos/genética , Sequenciamento Completo do Exoma/métodos , Anormalidades Múltiplas/diagnóstico , Pré-Escolar , Anormalidades do Olho/diagnóstico , Genes Recessivos , Humanos , Doenças Renais Císticas/diagnóstico , Masculino
3.
BMC Med Genet ; 21(1): 193, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008324

RESUMO

BACKGROUND: Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively. CASE PRESENTATION: A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing. CONCLUSION: A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Síndrome de Dandy-Walker/genética , Face/anormalidades , Doenças Hematológicas/genética , Hipoglicemia/genética , Proteínas de Neoplasias/genética , Deleção de Sequência , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Bases , Síndrome de Dandy-Walker/diagnóstico , Feminino , Testes Genéticos , Doenças Hematológicas/diagnóstico , Humanos , Hipoglicemia/diagnóstico , Recém-Nascido , Homologia de Sequência do Ácido Nucleico , Doenças Vestibulares/diagnóstico , Sequenciamento Completo do Exoma/métodos
4.
Tunis Med ; 98(5): 420-422, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548846

RESUMO

Cystic Fibrosis (CF) is a lethal autosomal recessive condition due to a defect at the level of the transmembrane conductance regulator gene which plays a role in cell homeostasis. Numerous mutations have been identified as the cause of this gene defect, with delF508 being one of the most common mutations in Tunisia. This is a case report describing, up to our knowledge, the second case of a patient with CF carrying a rare mutation: W19X. W19X is a nonsense mutation that has been previously identified in only one other Tunisian patient with CF. Since both incidence of this mutation have been described in Tunisia, it seems as if W19X is specific to Tunisian CF patient with significant morbidities. The information provided by this study contributes to defining the molecular spectrum of CF in Tunisia, in the aim of improving genetic testing and prenatal diagnosis.


Assuntos
Códon sem Sentido , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Fibrose Cística/diagnóstico , Fibrose Cística/patologia , Frequência do Gene , Testes Genéticos , Humanos , Triptofano/genética , Tunísia
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 509-513, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335874

RESUMO

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Testes Genéticos , Doenças Renais Císticas , Proteínas de Membrana , Diagnóstico Pré-Natal , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Variação Genética , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Gravidez
7.
Medicine (Baltimore) ; 99(15): e19751, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282736

RESUMO

RATIONALE: This case report expands the mutation and phenotypic spectra of Beaulieu-Boycott-Innes syndrome (BBIS), and will be valuable for mutation-based pre- and post-natal screening of BBIS when conducting a genetic diagnosis. PATIENT CONCERNS: A 4-year old boy from Guilin City, Guangxi Zhuang Autonomous Region, China, was referred to our clinic for clarification of his diagnosis because he showed moderate intellectual disability. DIAGNOSIS: Two novel compound heterozygous mutations of THOC6, c.664T>C (p.Trp222Arg) and c.945+1 G>A were identified in this patient by whole exome sequencing. The two mutations were evaluated as pathogenic and likely pathogenic respectively according to the American College of Medical Genetics guidelines. This is the first case displaying the BBIS phenotype reported in the Chinese population. These two mutations have not been reported previously. INTERVENTIONS: Symptomatic treatment and rehabilitation training for patients. OUTCOMES: The genetic cause of the disease was identified. The family received scientific genetic counseling. LESSONS: BBIS is a rare syndromic autosomal recessive disease with intellectual disability and it is normally difficult for clinicians to recognize it. Whole exome sequencing is an efficient way to identify the gene which causes a particular disease in patients.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Proteínas de Ligação a RNA/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/reabilitação , Anormalidades Múltiplas/terapia , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/reabilitação , Deficiências do Desenvolvimento/terapia , Facies , Aconselhamento Genético/normas , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/reabilitação , Deficiência Intelectual/terapia , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/reabilitação , Atrofia Muscular/terapia , Mutação/genética , Fenótipo , Síndrome , Sequenciamento Completo do Exoma/métodos
8.
Medicine (Baltimore) ; 99(16): e19813, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311999

RESUMO

RATIONALE: Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. PATIENT CONCERNS: The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. DIAGNOSIS: FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. INTERVENTIONS: The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). OUTCOMES: The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. LESSONS: As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.


Assuntos
Anormalidades Múltiplas/genética , Blefarofimose/diagnóstico , Contratura/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Cardiopatias Congênitas/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Hipertricose/congênito , Deficiência Intelectual/genética , Microcefalia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades da Pele/diagnóstico , Anormalidades Urogenitais/diagnóstico , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Grupo com Ancestrais do Continente Asiático/genética , Criança , Contratura/diagnóstico , Contratura/terapia , Erros de Diagnóstico , Facies , Genótipo , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/terapia , Hormônio do Crescimento/uso terapêutico , Cardiopatias Congênitas/cirurgia , Humanos , Hipertricose/diagnóstico , Hipertricose/etiologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/terapia , Masculino , Microcefalia/diagnóstico , Microcefalia/terapia , Mutação , Fenótipo , Resultado do Tratamento , Sequenciamento Completo do Exoma/métodos
9.
World Neurosurg ; 138: 461-467, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32200015

RESUMO

Caudal regression syndrome (CRS) represents a spectrum of clinical phenotypes with varying degrees of malformation of the lower body with involvement of structures deriving from all 3 layers of the trilaminar embryo. We review areas of active investigation in the diagnosis, etiology, epidemiology, and treatment of the disease with a focus on underlying genetics. CRS pathobiology is complex and multifactorial with a significant contribution from environmental factors as evidenced in twin studies. Contemporary genomic and genetic investigations in both human primary tissue and murine in vitro and in vivo models implicate various genes associated with caudal differentiation and neural cell migration in embryogenesis. A large number of identified targets center around the metabolic regulation of retinoic acid and its derivatives. Dysregulation of retinoic acid homeostasis has been associated with abnormal embryonic cell migration, differentiation, and organogenesis with resulting malformations and agenesis in both a laboratory and a clinical setting. There appears to be a significant overlap in potential genetic targets with CRS and other developmental syndromes with similar presentations, such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. CRS represents a spectrum of caudal developmental abnormalities with treatment options limited to mild and moderate expressions of disease. Continued research is necessary to further clarify mechanisms of disease pathobiology and complex polygenetic and environmental interaction. Despite this, progress has been made in identifying genetic targets and downstream effectors contributing to preclinical and clinical progression.


Assuntos
Anormalidades Múltiplas/genética , Genômica , Deformidades Congênitas dos Membros/genética , Malformações do Sistema Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Animais , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/patologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Tretinoína/metabolismo
10.
Int J Pediatr Otorhinolaryngol ; 133: 109971, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32179205

RESUMO

OBJECTIVE: Characterize patients with complete tracheal rings and tracheoesophageal fistula (TEF) and summarize management options. METHODS: A systematic review of patients under 18 years of age with complete tracheal rings and TEF was conducted. Authors were contacted for additional patient information and new cases were added. Patients with iatrogenic TEF and tracheal stenosis due to other causes were excluded. RESULTS: Sixteen patients with a median (IQR) follow-up of 10 months (3-12 months) were identified. All had a distal TEF with complete tracheal rings distal to the TEF. There were 10 (63%) type C esophageal atresia + TEF (EA/TEF), and 1 (6%) type D (5 missing data). Median (IQR) airway diameter was 2 mm (1.5-2.2 mm). Complete tracheal rings were diagnosed prior to TEF repair in 5 (31.3%) patients, after ≥1 failed extubation in 3 (12.5%) patients, and intra-operatively during respiratory distress in 1 patient. Ten patients (62.5%) were intubated with an endotracheal tube and one with a 6 Fr flexible aortic canula (5 missing data). Four patients with an endotracheal tube for TEF repair developed ventilatory problems. Complete tracheal rings were repaired in 9 (56%) patients (8 slide tracheoplasty, 1 pericardial patch) and followed conservatively in 3 (19%). One patient required tracheotomy. Four patients died. CONCLUSIONS: Complete tracheal rings with concurrent TEF is a rare entity that pose challenges for ventilatory management during operative repair. Bronchoscopy prior to TEF repair is critical to allow for proper preoperative planning.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Estenose Traqueal/diagnóstico , Estenose Traqueal/terapia , Fístula Traqueoesofágica/diagnóstico , Fístula Traqueoesofágica/terapia , Adolescente , Broncoscopia , Criança , Pré-Escolar , Terapia Combinada , Tratamento Conservador/métodos , Humanos , Lactente , Recém-Nascido , Intubação Intratraqueal , Assistência Perioperatória/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Estenose Traqueal/congênito , Fístula Traqueoesofágica/congênito , Traqueostomia , Traqueotomia , Resultado do Tratamento
11.
Taiwan J Obstet Gynecol ; 59(1): 123-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039779

RESUMO

OBJECTIVE: We present the prenatal diagnosis of a class II 1q21.1 microdeletion in monozygotic (MZ) twins with discordant phenotypes. CASE REPORT: A monochorionic diamniotic twin pair presented with discordant ultrasound anomalies; twin A had cardiovascular abnormalities, while twin B did not. No specific complications were noted in the twins during pregnancy. A single nucleotide polymorphism array revealed an identical class II 1q21.1 microdeletion inherited from a phenotypically normal mother and identified the twins as MZ. The deleted region encompassed both the proximal 1q21.1 thrombocytopenia absent radius syndrome region and the distal 1q21.1 recurrent microdeletion region. No other rare copy number variants (CNVs) were identified, and concordance was observed in the CNVs between the twins. CONCLUSION: Discordant cardiovascular abnormalities may occur in MZ twins carrying the same class II 1q21.1 microdeletion. Further studies involving discordant MZ twins are needed to determine the modifying factors of the phenotypic heterogeneity of the microdeletion.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Cardiovasculares/diagnóstico , Doenças em Gêmeos/diagnóstico , Megalencefalia/diagnóstico , Diagnóstico Pré-Natal/métodos , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/genética , Adulto , Anormalidades Cardiovasculares/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Variações do Número de Cópias de DNA , Doenças em Gêmeos/genética , Feminino , Humanos , Megalencefalia/genética , Fenótipo , Gravidez , Gravidez de Gêmeos/genética
12.
Hum Genet ; 139(4): 531-543, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030560

RESUMO

We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Transtornos Cromossômicos , Cromossomos Humanos/genética , Facies , Genes Dominantes , Deficiência Intelectual , Diagnóstico Pré-Natal , Anormalidades Dentárias , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Gravidez , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fluxo de Trabalho
13.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
14.
Otolaryngol Head Neck Surg ; 162(4): 554-558, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31959051

RESUMO

OBJECTIVE: Congenital ear anomalies are associated with congenital cardiac and renal defects. Renal ultrasounds, electrocardiogram, and echocardiogram can be utilized for diagnosis of these concurrent defects. No standard of care exists for the workup of patients with microtia. The goals of this study were to describe the utilization of diagnostic testing for cardiac and renal anomalies and to identify their prevalence in patients with microtia. STUDY DESIGN: Case series with chart review. SETTING: Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center. SUBJECTS AND METHODS: This study is an Institutional Review Board-approved retrospective review of consecutive patients born between 2002 and 2016 who were diagnosed with microtia and seen in the otolaryngology clinic at a tertiary care children's hospital. Demographics, sidedness and grade of microtia, comorbid diagnoses, and details of renal and cardiovascular evaluations were recorded. Factors associated with retroperitoneal ultrasound and cardiac testing were assessed with logistic regression. RESULTS: Microtia was present in 102 patients, and 98 patients were included as they received follow-up. Microtia was associated with craniofacial syndrome in 34.7% of patients. Renal ultrasound was performed in 64.3% of patients, and 12.9% of patients with ultrasounds had renal aplasia. Cardiac workup (electrocardiogram or echocardiogram) was completed in 60.2% of patients, and of this subset, 54.2% had a congenital heart defect. CONCLUSION: Diagnostic testing revealed renal anomalies and cardiac defects in patients with isolated microtia at a higher rate than in the general population. This suggests the need for further evaluation of the role of routine screening in patients with microtia.


Assuntos
Anormalidades Múltiplas/diagnóstico , Microtia Congênita/complicações , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Rim/anormalidades , Anormalidades Múltiplas/epidemiologia , Adolescente , Criança , Pré-Escolar , Técnicas e Procedimentos Diagnósticos/estatística & dados numéricos , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Estudos Retrospectivos
15.
Z Geburtshilfe Neonatol ; 224(3): 153-159, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31853915

RESUMO

Within 4 years (2014-2017), we genetically diagnosed 2 newborns with Kagami-Ogata syndrome (OMIM #608149). As fetuses they exhibited prenatal polyhydramnios and in 1 case hepatomegaly. After birth, the newborns suffered from respiratory distress. Typical phenotypic features, such as muscular hypotonia, a protruding philtrum, full cheeks and a depressed nasal bridge, were present. Chest X-rays revealed coat-hanger ribs and a bell-shaped thorax, suggestive of the entity. Kagami-Ogata syndrome is caused by an aberrant gene expression of chromosome 14 and was first described in 1991. Possible causes are paternal uniparental disomy of chromosome 14, epimutations and microdeletions. Approximately 70 cases have been reported in the literature, with 34 comprising the original cohort of M. Kagami and T. Ogata. The incidence of the disease is unknown. Patients often manifest a developmental delay and an intellectual disability, although in the meantime cases with milder clinical courses have been described. In the cohort of Kagami and Ogata 3 patients developed hepatoblastoma, which is a common feature in another imprinting disorder, namely the Beckwith-Wiedemann syndrome. Therefore, hepatoblastoma should be considered in follow-up examinations.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Deficiência Intelectual/genética , Costelas/anormalidades , Tórax/anormalidades , Dissomia Uniparental/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Transtornos Cromossômicos/diagnóstico , Feminino , Impressão Genômica , Humanos , Recém-Nascido , Poli-Hidrâmnios , Gravidez , Costelas/diagnóstico por imagem , Tórax/diagnóstico por imagem
16.
Am J Obstet Gynecol ; 221(6): B16-B18, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31787159

Assuntos
Ossos do Carpo/anormalidades , Deformidades Congênitas dos Membros/diagnóstico por imagem , Rádio (Anatomia)/anormalidades , Polegar/anormalidades , Anormalidades Induzidas por Medicamentos/diagnóstico , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Amniocentese , Síndrome de Bandas Amnióticas/complicações , Síndrome de Bandas Amnióticas/diagnóstico , Canal Anal/anormalidades , Ossos do Carpo/diagnóstico por imagem , Amostra da Vilosidade Coriônica , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Diagnóstico Diferencial , Esôfago/anormalidades , Anemia de Fanconi/complicações , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Feminino , Testes Genéticos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/genética , Humanos , Rim/anormalidades , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas das Extremidades Inferiores/complicações , Deformidades Congênitas das Extremidades Inferiores/diagnóstico , Deformidades Congênitas das Extremidades Inferiores/genética , Análise em Microsséries , Gravidez , Rádio (Anatomia)/diagnóstico por imagem , Coluna Vertebral/anormalidades , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Polegar/diagnóstico por imagem , Traqueia/anormalidades , Síndrome da Trissomia do Cromossomo 13/complicações , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Ultrassonografia Pré-Natal , Deformidades Congênitas das Extremidades Superiores/complicações
17.
Anatol J Cardiol ; 22(6): 325-331, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31789610

RESUMO

OBJECTIVE: We aimed to review symptoms, findings, surgical treatment options, short- and mid-term outcomes, and reoperation rate of patients diagnosed with of left coronary artery from the pulmonary artery (ALCAPA) of an anomalous origin in our institution. METHODS: From May 2000 to March 2018, 33 patients who had left coronary artery originating from the pulmonary artery were retrospectively examined. The clinical features of patients, diagnostic tools and their efficacy, outcomes of surgical repair, and problems during follow-up were evaluated. RESULTS: Thirty-three patients (22 females, 11 males) were included in the study. At the time of surgery, the median age and weight of patients were 6 months (minimum/maximum, 1-166 months) and 6.5 kg (minimum/maximum, 3-38.5 kg), respectively. The mean follow-up was 5±3.5 years (range, 1-16 years). Dyspnea, tachypnea, diaphoresis, prolonged feeding time, and developmental delay were common presenting signs and symptoms. It was determined that all the patients who were diagnosed at another center reached our center for surgical treatment within 1 month. Twenty-three (69.7%) patients had pathologic Q wave with anterior and/or anterolateral myocardial infarction signs on an electrocardiogram (ECG), whereas 22 (66.6%) patients had ST-T segment changes. Twenty-one (63.6%) patients had cardiomegaly on the telecardiogram. A reimplantation surgery was performed to 22 patients and 10 patients underwent the Takeuchi procedure. In addition to ALCAPA repair, 5 patients needed mitral valve plasty. Atrial septal defect (ASD) and ventricular septal defect (VSD) were closed in one patient, and Tetralogy of Fallot was totally corrected in another. At discharge, there was a significant improvement in left ventricular (LV) systolic functions. At the last visit, all patients had normal LV systolic functions except four who had mild dysfunction. The mean follow-up of the four patients was 2.8 years. In the early postoperative period, complications were seen in 10 patients. Five patients died in the early postoperative period, while one patient died 9 months after the ALCAPA surgery because of low cardiac output syndrome that developed after mitral repair. CONCLUSION: Patients with ALCAPA commonly present with congestive heart failure symptoms. When the diagnosis is confirmed in these patients, surgical treatment should not be delayed. The availability of surgical center and surgery outcomes for ALCAPA diagnosed patients are comparable with other countries, but the delay in the diagnosis of disease is still a problem in our country.


Assuntos
Anomalias dos Vasos Coronários/diagnóstico , Vasos Coronários , Artéria Pulmonar/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/cirurgia , Adolescente , Criança , Pré-Escolar , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/mortalidade , Anomalias dos Vasos Coronários/cirurgia , Ecocardiografia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Turquia/epidemiologia , Gravação em Vídeo
18.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 46(4): 163-166, oct.-dic. 2019. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-184305

RESUMO

Los trastornos relacionados con mutaciones del gen IRF6, comprenden desde una afectación casi asintomática con la única presencia de hoyuelos labiales que son la manifestación más sutil del síndrome de van der Woude, hasta manifestaciones congénitas graves que incluyen anomalías faciales, musculoesqueléticas y genitourinarias que corresponden al síndrome de pterigium poplíteo. Pese a que existe cierta relación fenotipo-genotipo entre las mutaciones del gen IRF6, estas tienen una penetrancia incompleta y una expresión variable, inter e intrafamiliar


The disorders related to IRF6 encompass a spectrum from an almost asymptomatic affectation, with the only presence of isolated lip pits, which are a mild presentation of van der Woude syndrome, to the presence in the other extreme, of congenital manifestations that include facial anomalies, musculoskeletal and genitourinary malformations, corresponding to popliteal pterygium syndrome. Although there is a certain phenotype-genotype relationship between mutations of the IRF6 gene, such mutations have incomplete penetrance and variable inter-and intra-familial expression


Assuntos
Humanos , Feminino , Gravidez , Adulto , Anormalidades Múltiplas/diagnóstico , Fenda Labial/diagnóstico , Dedos/anormalidades , Sindactilia/diagnóstico , Mutação , Fenda Labial/genética , Deformidades Congênitas das Extremidades Inferiores/diagnóstico , Feto/anormalidades
19.
Neonatal Netw ; 38(6): 329-335, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31712397

RESUMO

With the rise in genetic screening both pre- and postnatally, new variances in genes are being recognized. Some are of unknown significance, while other known genetic expressions have obvious phenotypical expressions. Transient neonatal diabetes mellitus is a result of the duplication of chromosome 6q24, but little is known about the phenotypic expression of a triplication of chromosome 6q24. This case study presents an infant with a postnatally diagnosed triplication of chromosome 6q24, meconium pseudocyst, and multiple congenital anomalies with unknown genetic significance.


Assuntos
Anormalidades Múltiplas/diagnóstico , Cistos/congênito , Diabetes Mellitus/diagnóstico , Mecônio , Cistos/diagnóstico , Humanos , Recém-Nascido , Masculino
20.
Diagn Pathol ; 14(1): 123, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684969

RESUMO

BACKGROUND: Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. CASE PRESENTATION: Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. CONCLUSION: Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.


Assuntos
Anormalidades Múltiplas/genética , Hidrolases de Éster Carboxílico/genética , Deficiência Intelectual/genética , Mutação/genética , Distúrbios do Metabolismo do Fósforo/genética , Receptores de Superfície Celular/genética , Anormalidades Múltiplas/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Linhagem , Fenótipo , Distúrbios do Metabolismo do Fósforo/diagnóstico
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