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1.
Am J Med Genet A ; 179(8): 1543-1546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207089

RESUMO

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

2.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
4.
Am J Med Genet A ; 179(4): 668-673, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30811827

RESUMO

In 2011, biallelic loss-of-function variants in the interleukin receptor 11 alpha gene IL11RA were found to be associated with a Crouzon-like craniosynostosis syndrome with associated dental anomalies (CRSDA). Since then, a total of 41 similar patients have been reported with IL11RA variants. We report two adult brothers diagnosed with Crouzon syndrome as children, in which the clinical diagnosis of CRSDA was made on reevaluation. Laboratory testing detected biallelic IL11RA variants, c.916_924dup (p.Thr306_Ser308dup) and c.781C > T (p.Arg261Cys), both of which have now been reported in other families. Protein modeling and conservation analysis show that these two mutation sites cluster together near a WSXWS motif that likely plays a significant role in regulating IL11RA protein function. Population analysis from gnomAD shows that Non-Finnish Europeans (similar to ethnicity of this family), have an allele frequency for p.Thr306_Ser308dup of 0.014% and p.Arg261Cys of 0.008%. We found other ethnicities have functional IL11RA missense variants at higher frequencies. With this report, we provide a summary of the clinical findings including details of middle ear anomalies associated with conductive hearing loss. We also provide data supporting the populations at risk for this condition to increase recognition and diagnosis of this rare autosomal recessive craniosynostosis syndrome.

6.
Pediatr Neurol ; 2018 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-30327238

RESUMO

BACKGROUND: Infantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. METHODS: We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. RESULTS: Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. CONCLUSIONS: NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.

7.
Am J Hum Genet ; 102(6): 1158-1168, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861105

RESUMO

ßIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into ßIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na+ channels and no nodal KCNQ2 K+ channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and ßI spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ßIV spectrin at nodes of Ranvier, AnkR and ßI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K+ channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction.

8.
Am J Med Genet A ; 170(7): 1780-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27112432

RESUMO

Troyer syndrome is a complex hereditary spastic paraplegia (HSP) due to a mutation in SPG20 first reported in the Old Amish population. A genetic mutation in SPG20 is responsible for a loss of function of the protein spartin in this disease. Since its initial report, this syndrome has also been reported in Turkish and Omani families. Here we report the case of three patients of Filipino descent with Troyer syndrome. Whole exome sequencing (WES) identified a homozygous mutation c.364_365delAT which predicts p.Met122Valfs*2 in SPG20. This is the same mutation identified in affected patients from the Omani and Turkish families, and is the first report of this syndrome in the Filipino population. Although Troyer syndrome has characteristic phenotypic manifestations it is likely underdiagnosed due to its rarity and we expect that WES will lead to identifying this disease in other individuals. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas/genética , Paraplegia Espástica Hereditária/genética , Criança , Exoma/genética , Feminino , Humanos , Masculino , Mutação , Paraplegia Espástica Hereditária/epidemiologia , Paraplegia Espástica Hereditária/fisiopatologia
9.
Am J Med Genet A ; 167A(11): 2780-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26227324

RESUMO

Timothy syndrome (TS) is a rare genetic condition that associates long QT syndrome, structural heart defects, dysmorphic facial features, syndactyly, seizures, developmental delay, and autism. Timothy syndrome type 1 is caused by a recurrent de novo mutation (p.Gly406Arg) in exon 8A of the L-type calcium channel gene CACNA1C. Timothy syndrome type 2 was originally reported to be associated with a more severe cardiac phenotype but without syndactyly. Timothy syndrome type 2 is caused by mutation in an alternatively spliced exon 8 of the CACNA1C gene. Other mutations in CACNA1C are also reported with long QT syndrome with and without syndromic features overlapping that described in Timothy syndrome. The purpose of this report is to describe the presentation, physical features and natural history of a 4-year-old girl with Timothy syndrome type 2 due to the recurrent p.Gly406Arg mutation in exon 8 of CACNA1C. She has similar facial features to Timothy syndrome type 1 without syndactyly. She is developmentally delayed without autism. She recently had her first episode of torsade de pointes associated with febrile illness and hypoglycemia. The findings in this case provide further information about the phenotype and natural history of CACNA1C exon 8 mutation and together with previously reported cases of Timothy syndrome question whether the clinical and molecular distinction between Timothy syndromes types 1 and 2 remains clinically useful.


Assuntos
Transtorno Autístico/complicações , Transtorno Autístico/diagnóstico , Anormalidades Craniofaciais/complicações , Dedos/anormalidades , Síndrome do QT Longo/complicações , Sistema Nervoso/patologia , Sindactilia/complicações , Sindactilia/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome do QT Longo/diagnóstico , Gravidez
10.
Am J Med Genet A ; 167(7): 1582-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25900371

RESUMO

Tetrasomy 20p is a very rare chromosome abnormality, with only two single cases previously reported in the literature, both fetuses with multiple congenital anomalies, osteopenia, and fractures. We report on the first case of mosaic tetrasomy 20p in a 13-year-old male. Amniocentesis karyotype showed mosaicism (73% of cells) for a supernumerary marker chromosome, an isodicentric chromosome 20p. At birth, cord blood karyotype was normal in all cells but uroepithelial cells showed the marker chromosome in 30% of cells analyzed. Chromosomal single nucleotide polymorphism (SNP) microarray using buccal cells confirmed the previous result with mosaicism estimated at 59% of cells. His course has been complicated by profound osteoporosis with recurrent nontraumatic fractures and vertebral compression leading to significant disability. This report describes the phenotype and evaluation of mosaic pure tetrasomy 20p syndrome and compares to nonmosaic tetrasomy 20p and trisomy 20p syndromes, both of which have been previously reported in association with osteopenia and fractures. The pathophysiology of osteoporosis in tetrasomy 20p is unknown. We hypothesize that overexpression of bone morphogenetic protein 2 may be the underlying mechanism of osteoporosis and recurrent fractures.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 20/genética , Fraturas Espontâneas/genética , Mosaicismo , Osteoporose/genética , Tetrassomia/genética , Adolescente , Marcadores Genéticos/genética , Humanos , Cariótipo , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único/genética , Urotélio/metabolismo
11.
Am J Med Genet A ; 167A(1): 142-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25402239

RESUMO

The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity.


Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/patologia , Peso Corporal , Impressão Genômica , Dissomia Uniparental/genética , Dissomia Uniparental/patologia , Cefalometria , Criança , Feminino , Humanos , Lactente , Masculino
12.
Am J Med Genet A ; 164A(11): 2814-21, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25250515

RESUMO

The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis.


Assuntos
Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Fenótipo , Anormalidades Múltiplas , Síndrome de Costello/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Síndrome de Noonan/genética , Diagnóstico Pré-Natal
14.
Am J Med Genet A ; 164A(8): 2036-42, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24719372

RESUMO

There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras-MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii's largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts.


Assuntos
Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Fenótipo , Displasia Ectodérmica/genética , Displasia Ectodérmica/terapia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/terapia , Feminino , Idade Gestacional , Cabelo/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/terapia , Humanos , Lactente , Recém-Nascido , MAP Quinase Quinase 2/genética , Masculino , Mutação , Pele/patologia
15.
Am J Hum Genet ; 94(5): 734-44, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24726473

RESUMO

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.


Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Blefarofimose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Deformidades Congênitas da Mão/genética , Canais Iônicos/genética , Oftalmoplegia/genética , Doenças Retinianas/genética , Anormalidades Múltiplas/patologia , Aracnodactilia/patologia , Artrogripose/patologia , Blefarofimose/patologia , Criança , Pré-Escolar , Fissura Palatina/patologia , Pé Torto Equinovaro/patologia , Doenças do Tecido Conjuntivo/patologia , Contratura/patologia , Exoma/genética , Feminino , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Mutação , Oftalmoplegia/patologia , Linhagem , Doenças Retinianas/patologia
16.
Am J Med Genet A ; 158A(9): 2353-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22887355

RESUMO

Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present.


Assuntos
Artrogripose/etiologia , Mitocôndrias/fisiologia , Humanos , Lactente , Masculino
17.
Genet Med ; 14(5): 508-14, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22241097

RESUMO

PURPOSE: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low-copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. METHODS: We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. RESULTS: The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father. CONCLUSION: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome.


Assuntos
Cromossomos Humanos Par 17/genética , Duplicação Gênica , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Feminino , Genes da Neurofibromatose 1 , Recombinação Homóloga , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Neurofibroma/genética , Fenótipo , Duplicações Segmentares Genômicas/genética , Deleção de Sequência , Adulto Jovem
18.
PLoS One ; 6(11): e27348, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22132097

RESUMO

Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal ß-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/genética , Atetose/complicações , Coreia/complicações , Epilepsia/complicações , Epilepsia/genética , Transtornos de Aprendizagem/complicações , Mutação/genética , 3-Hidroxiacil-CoA Desidrogenases/química , Adulto , Sequência de Aminoácidos , Atetose/enzimologia , Atetose/genética , Atetose/urina , Sequência de Bases , Ácidos Carboxílicos/urina , Criança , Pré-Escolar , Coreia/enzimologia , Coreia/genética , Coreia/urina , Análise Mutacional de DNA , Eletroencefalografia , Transporte de Elétrons , Epilepsia/enzimologia , Epilepsia/urina , Feminino , Fibroblastos/enzimologia , Humanos , Recém-Nascido , Transtornos de Aprendizagem/enzimologia , Transtornos de Aprendizagem/genética , Transtornos de Aprendizagem/urina , Masculino , Redes e Vias Metabólicas , Mitocôndrias/enzimologia , Dados de Sequência Molecular , Polimorfismo de Fragmento de Restrição , Gravidez
19.
Nat Genet ; 43(11): 1074-81, 2011 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-21964572

RESUMO

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat-mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.


Assuntos
Rearranjo Gênico , Genoma Humano , Sequências Repetitivas de Ácido Nucleico , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo , Polimorfismo de Nucleotídeo Único
20.
Am J Med Genet A ; 155A(9): 2045-59, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21815262

RESUMO

Aside from gastroschisis and omphalocele, major defects of the ventral body (thoracoabdominal) wall are relatively uncommon and almost universally lethal. They are most often associated with other anomalies including those of the limbs that may range from amelia to mild positional deformations, unusual craniofacial malformations, and a variety of visceral abnormalities that include the heart, lungs, genitourinary system, and gut. This complex of ventral wall anomalies has been discussed under a broad and changing nomenclature that has included amniotic band disruption complex, amnion rupture sequence, limb-body wall defect (or complex), and simply body wall complex. Three major theories have been suggested to explain this complex: early amnion rupture (operating through uterine pressure and/or disruption by amniotic bands), vascular compromise (primarily hypoperfusion), and an early intrinsic defect of the developing embryo. We present four patients that illustrate the spectrum of ventral body wall defects, and from there critique the current hypotheses of pathogenesis. We conclude that this association of malformations originates as early as the embryonic disc stage, and that some of the observed associated anomalies are secondary complications of the primary disturbance in embryogenesis. We propose a new explanation for the atypical facial clefts and cranial malformations that are often observed.


Assuntos
Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/patologia , Anormalidades Craniofaciais , Gastrosquise , Deformidades Congênitas dos Membros , Parede Abdominal/anormalidades , Parede Abdominal/embriologia , Síndrome de Bandas Amnióticas , Ectromelia , Extremidades/embriologia , Feminino , Humanos , Recém-Nascido , Masculino
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