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1.
Clin Genet ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580568

RESUMO

Patient-reported outcome measures (PROMs) are increasingly utilized as endpoints in clinical trials. The Short Form Health Survey-12 (SF-12v2) is a generic PROM for adults. We sought to evaluate the validity of SF-12v2 in adults with osteogenesis imperfecta (OI). Physical and mental health-related quality of life (HRQoL) were assessed in a large cohort of adults in a multicenter, observational, natural history study. Physical HRQoL scores were correlated with the Gillette Functional Assessment Questionnaire (GFAQ). We calculated sample sizes required in clinical trials with crossover and parallel-group designs to detect clinically meaningful changes in physical HRQoL. Three hundred and two adults with OI types I, III, and IV were enrolled. Physical HRQoL scores in the study population were lower than population norms. Physical HRQoL scores moderately correlated with GFAQ for OI types I and IV. We found no correlations between mental and physical HRQoL. From a clinical trial readiness perspective, we show that SF-12v2 reliably measures physical function in adults with OI and can be utilized in crossover trials to detect meaningful physical HRQoL changes with small sample sizes. This study shows that SF-12v2 can be used to measure changes in physical HRQoL in response to interventions in OI.

2.
Am J Med Genet A ; 185(3): 916-922, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369125

RESUMO

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

3.
Mol Genet Genomic Med ; 8(10): e1383, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32692472

RESUMO

BACKGROUND: CACNA1A variants have been described in several disorders that encompass a wide range of neurologic phenotypes, including hemiplegic migraine, ataxia, cognitive delay, and epilepsy. To date, ischemic stroke caused by a CACNA1A variant has only been reported once in the literature. METHODS: We describe a 4-year-old female with recurrent ischemic strokes beginning at 6 weeks of age, intractable epilepsy, and significant global developmental delay. Exome sequencing (ES) was completed for her evaluation. RESULTS: We found a novel de novo, likely pathogenic variant, p.Leu1692Gln in CACNA1A by ES. The substitution affects a leucine residue that is highly conserved in species from fish to primates. CONCLUSION: We present the second case of recurrent ischemic strokes in a patient with CACNA1A mutation. Our findings expand the phenotypic heterogeneity related to Cav 2.1 (P/Q-type) calcium channel dysfunction and suggest consideration of CACNA1A disorder in evaluation of pediatric strokes.

4.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
5.
Am J Med Genet A ; 182(8): 1960-1966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449285

RESUMO

The mitochondrial aconitase gene (ACO2) encodes an enzyme that catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Biallelic variants in ACO2 are purported to cause two distinct disorders: infantile cerebellar-retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic ACO2 variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic ACO2 variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in ACO2; c.[487G>T];[1894G>A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic ACO2 variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in ACO2 can cause the milder OPA9 phenotype, and that the OPA9-related ACO2 variants identified to date are distinct from those that cause ICRD.

6.
Am J Med Genet A ; 182(6): 1387-1399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32233023

RESUMO

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

7.
Sci Adv ; 5(9): eaax2166, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31579823

RESUMO

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Variação Genética , Neurogênese/genética , Proteínas de Ligação a RNA/genética , Transmissão Sináptica/genética , Adolescente , Animais , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Linhagem , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Sinapses/genética , Sinapses/metabolismo , Adulto Jovem
8.
Am J Med Genet A ; 179(12): 2459-2468, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520464

RESUMO

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B0 AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B0 AT1 in the renal apical brush bordered epithelium. Collectrin deficient mice have severe aminoaciduria. However, the phenotype associated with collectrin deficiency in humans has not been reported. Here we report two patients, an 11-year-old male who is hemizygous for a small, interstitial deletion on Xp22.2 that encompasses CLTRN and a 22-year-old male with a deletion spanning exons 1 to 3 of CLTRN. Both of them present with neuropsychiatric phenotypes including autistic features, anxiety, depression, compulsions, and motor tics, as well as neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease and treatment with niacin supplementation. Plasma amino acids were normal in both patients. One patient had low 5-hydroxyindoleacetic acid levels, a serotoninergic metabolite. We explored the expression of collectrin in the murine brain and found it to be particularly abundant in the hippocampus, brainstem, and cerebellum. We propose that collectrin deficiency in humans can be associated with aminoaciduria and a clinical picture similar to that seen in Hartnup disease. Further studies are needed to explore the role of collectrin deficiency in the neurological phenotypes.


Assuntos
Deleção de Genes , Doença de Hartnup/diagnóstico , Doença de Hartnup/genética , Mutação com Perda de Função , Glicoproteínas de Membrana/genética , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Animais , Criança , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Adulto Jovem
9.
Genet Med ; 21(11): 2453-2461, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30992551

RESUMO

PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.


Assuntos
Metilação de DNA/genética , Diabetes Mellitus/embriologia , Doenças Fetais/genética , Alelos , Biomarcadores , Ilhas de CpG/genética , Complicações do Diabetes/genética , Diabetes Mellitus/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Locos de Características Quantitativas/genética
11.
Eur J Hum Genet ; 27(4): 563-573, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30622330

RESUMO

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.


Assuntos
GTP Fosfo-Hidrolases/genética , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/genética , Proteínas de Peixe-Zebra/genética , Animais , Padronização Corporal/genética , Desenvolvimento Embrionário/genética , Feminino , Estudos de Associação Genética , Genoma Humano/genética , Genômica , Cardiopatias Congênitas/fisiopatologia , Síndrome de Heterotaxia/fisiopatologia , Humanos , Masculino , Peroxidases/genética , Sequenciamento Completo do Exoma , Peixe-Zebra/genética
12.
J Pediatr ; 202: 206-211.e2, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30172441

RESUMO

OBJECTIVE: To determine the prevalence, spectrum, and prognostic significance of copy number variants of undetermined significance (cnVUS) seen on chromosomal microarray (CMA) in neonates with hypoplastic left heart syndrome (HLHS). STUDY DESIGN: Neonates with HLHS who presented to Texas Children's Hospital between June 2008 and December 2016 were identified. CMA results were abstracted and compared against copy number variations (CNVs) in ostensibly healthy individuals gathered from the literature. Findings were classified as normal, consistent with a known genetic disorder, or cnVUS. Survival was then compared using Kaplan-Meier analysis. Secondary outcomes included tracheostomy, feeding tube at discharge, cardiac arrest, and extracorporeal membrane oxygenation (ECMO). RESULTS: Our study cohort comprised 105 neonates with HLHS, including 70 (66.7%) with normal CMA results, 9 (8.6%) with findings consistent with a known genetic disorder, and 26 (24.7%) with a cnVUS. Six of the 26 (23.0%) neonates with a cnVUS had a variant that localized to a specific region of the genome seen in the healthy control population. One-year survival was 84.0% in patients with a cnVUS, 68.3% in those with normal CMA results, and 33.3% in those with a known genetic disorder (P = .003). There were no significant differences in secondary outcomes among the groups, although notably ECMO was used in 15.7% of patients with normal CMA and was not used in those with cnVUS and abnormal results (P = .038). CONCLUSIONS: Among children with HLHS, cnVUSs detected on CMA are common. The cnVUSs do not localize to specific regions of the genome, and are not associated with worse outcomes compared with normal CMA results.


Assuntos
Causas de Morte , Variações do Número de Cópias de DNA/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Procedimentos Cirúrgicos Cardíacos/métodos , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/métodos , Feminino , Hospitais Pediátricos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico , Síndrome do Coração Esquerdo Hipoplásico/terapia , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Cuidados Paliativos , Prognóstico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Texas
13.
Genet Med ; 20(7): 708-716, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29693650

RESUMO

PURPOSE: Benzoate and phenylbutyrate are widely used in the treatment of urea cycle disorders, but detailed studies on pharmacokinetics and comparative efficacy on nitrogen excretion are lacking. METHODS: We conducted a randomized, three-arm, crossover trial in healthy volunteers to study pharmacokinetics and comparative efficacy of phenylbutyrate (NaPB; 7.15 g•m-2BSA•day-1), benzoate (NaBz; 5.5 g•m-2BSA•day-1), and a combination of two medications (MIX arm; 3.575 g NaPB and 2.75 g NaBz•m-2BSA•day-1) on nitrogen excretion. Stable isotopes were used to study effects on urea production and dietary nitrogen disposal. RESULTS: The conjugation efficacy for both phenylbutyrate and benzoate was 65%; conjugation was superior at the lower dose used in the MIX arm. Whereas NaPB and MIX treatments were more effective at excreting nitrogen than NaBz, nitrogen excretion as a drug conjugate was similar between phenylbutyrate and MIX arms. Nitrogen excreted per USD was higher with combination therapy compared with NaPB. CONCLUSION: Phenylbutyrate was more effective than benzoate at disposing nitrogen. Increasing phenylbutyrate dose may not result in higher nitrogen excretion due to decreased conjugation efficiency at higher doses. Combinatorial therapy with phenylbutyrate and benzoate has the potential to significantly decrease treatment cost without compromising the nitrogen disposal efficacy.


Assuntos
Benzoatos/farmacocinética , Fenilbutiratos/farmacocinética , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adulto , Benzoatos/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Nitrogênio/metabolismo , Fenilbutiratos/farmacologia , Ureia/metabolismo
14.
Genome Med ; 9(1): 95, 2017 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29089047

RESUMO

BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. RESULTS: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95% confidence interval 2.5-6.5). CONCLUSIONS: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.


Assuntos
Cardiopatias Congênitas/genética , Feminino , Heterogeneidade Genética , Humanos , Padrões de Herança , Masculino , Sequenciamento Completo do Exoma
15.
JAMA Pediatr ; 171(12): e173438, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-28973083

RESUMO

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children's Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Unidades de Terapia Intensiva Pediátrica , Sequenciamento Completo do Exoma/métodos , Adulto , Cuidados Críticos/métodos , Gerenciamento Clínico , Exoma , Aconselhamento Genético/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Humanos , Lactente , Cuidado do Lactente/métodos , Recém-Nascido , Tempo de Internação/estatística & dados numéricos , Estudos Retrospectivos , Texas
16.
Am J Med Genet A ; 173(8): 2176-2188, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28653806

RESUMO

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.


Assuntos
Variações do Número de Cópias de DNA/genética , Cardiopatias Congênitas/genética , Coração/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genômica , Genótipo , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
PLoS One ; 12(4): e0175962, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28414775

RESUMO

By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.


Assuntos
Antígenos de Neoplasias/genética , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Deficiência Intelectual/genética , Proteínas de Neoplasias/genética , Fatores de Terminação de Peptídeos/genética , Deleção de Sequência/genética , Criança , Pré-Escolar , Duplicação Cromossômica/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Inativação do Cromossomo X/genética
18.
J Nutr ; 147(4): 549-555, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28275102

RESUMO

Background: Glutamine is considered the main precursor for citrulline synthesis in many species, including humans. The transfer of 15N from 2-[15N]-glutamine to citrulline has been used as evidence for this precursor-product relation. However, work in mice has shown that nitrogen and carbon tracers follow different moieties of glutamine and that glutamine contribution to the synthesis of citrulline is minor. It is unclear whether this small contribution of glutamine is also true in other species.Objective: The objective of the present work was to determine the contribution of glutamine to citrulline production by using nitrogen and carbon skeleton tracers in multiple species.Methods: Humans (n = 4), pigs (n = 5), rats (n = 6), and mice (n = 5) were infused with l-2-[15N]- and l-[2H5]-glutamine and l-5,5-[2H2]-citrulline. The contribution of glutamine to citrulline synthesis was calculated by using different ions and fragments: glutamine M+1 to citrulline M+1, 2-[15N]-glutamine to 2-[15N]-citrulline, and [2H5]-glutamine to [2H5]-citrulline.Results: Species-specific differences in glutamine and citrulline fluxes were found (P < 0.001), with rats having the largest fluxes, followed by mice, pigs, and humans (all P < 0.05). The contribution of glutamine to citrulline as estimated by using glutamine M+1 to citrulline M+1 ranged from 88% in humans to 46% in pigs. However, the use of 2-[15N]-glutamine and 2-[15N]-citrulline as precursor and product yielded values of 48% in humans and 28% in pigs. Furthermore, the use of [2H5]-glutamine to [2H5]-citrulline yielded lower values (P < 0.001), resulting in a contribution of glutamine to the synthesis of citrulline of ∼10% in humans and 3% in pigs.Conclusions: The recycling of the [15N]-glutamine label overestimates the contribution of glutamine to citrulline synthesis compared with a tracer that follows the carbon skeleton of glutamine. Glutamine is a minor precursor for the synthesis of citrulline in humans, pigs, rats, and mice.


Assuntos
Citrulina/biossíntese , Glutamina/sangue , Adulto , Animais , Isótopos de Carbono , Deutério , Feminino , Humanos , Marcação por Isótopo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Isótopos de Nitrogênio , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos
19.
Cold Spring Harb Mol Case Stud ; 3(2): a000984, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28299356

RESUMO

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in PLXND1 and REV3L, we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (TUBB3), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in TUBB3 have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.


Assuntos
Síndrome de Möbius/genética , Tubulina (Proteína)/genética , Criança , Pré-Escolar , Estudos de Coortes , Exoma , Oftalmopatias Hereditárias/genética , Paralisia Facial/congênito , Paralisia Facial/genética , Feminino , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/genética , Doenças Musculares/genética , Mutação , Transtornos da Motilidade Ocular/genética , Oftalmoplegia/genética , Doenças Orbitárias/genética , Linhagem , Tubulina (Proteína)/metabolismo , Sequenciamento Completo do Exoma
20.
J Med Genet ; 54(1): 47-53, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27550220

RESUMO

BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects. METHODS: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis. RESULTS: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother. CONCLUSIONS: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.


Assuntos
Cardiopatias Congênitas/genética , Ventrículos do Coração/patologia , Proteínas Associadas à Matriz Nuclear/genética , Fatores de Transcrição de Octâmero/genética , Proteínas de Ligação a RNA/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Exoma/genética , Cardiopatias Congênitas/patologia , Humanos , Lactente , Masculino
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