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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Genet Med ; 23(4): 637-644, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33244166

RESUMO

PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.


Assuntos
Deficiência Intelectual , Complexo Mediador/genética , Retardo Mental Ligado ao Cromossomo X , Retinite Pigmentosa , Adulto , Colestase , Fissura Palatina , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Fenótipo , Adulto Jovem
3.
Am J Med Genet A ; 182(3): 437-440, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833187

RESUMO

Catel-Manzke syndrome is characterized by hand anomalies, Robin sequence, cardiac defects, joint hyperextensibility, and characteristic facial features. Approximately 40 patients with Catel-Manzke have been reported, all with the pathognomonic bilateral or unilateral hyperphalangy caused by an accessory bone between the second metacarpal and proximal phalanx known as Manzke dysostosis. Here we present the first case of molecularly confirmed Catel-Manzke syndrome with Robin sequence but without Manzke dysostosis.


Assuntos
Deformidades Congênitas da Mão/genética , Hidroliases/genética , Disostose Mandibulofacial/genética , Síndrome de Pierre Robin/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/patologia , Humanos , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/patologia , Mutação/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/patologia
4.
Am J Med Genet A ; 173(2): 414-420, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28102598

RESUMO

Relatively few patients with Cornelia de Lange syndrome (CdLS) due to SMC1A mutation have been reported, limiting understanding of the full extent of the phenotype. Compared to children with classic NIPBL-associated CdLS, patients with SMC1A-associated CdLS have a milder physical phenotype with prominent intellectual disability, high rate of cleft palate and absence of limb reductions. We present a patient with SMC1A-associated CdLS who had typical features including developmental delay, seizure disorder, feeding difficulties, hirsutism, and cleft palate. She also was found to have three novel features: (i) left ventricular non-compaction (LVNC) cardiomyopathy; (ii) microform cleft lip; and (iii) severe hyperopia and astigmatism. These features have implications regarding potential insight into the pathogenesis of the disorder, screening, and medical management. Hypertrophic cardiomyopathy has previously been reported in SMC1A-associated CdLS, but to our knowledge this is the first reported child with LVNC. Previous reports have included children with isolated clefts of the palate without involvement of the lip. When cleft palate alone is associated with a disorder, the underlying pathophysiology for clefting is sometimes secondary due to mechanical blocking of the fusion of the palatal shelves with the developing tongue. The presence of microform cleft lip in this patient suggests that the pathophysiology of clefting in SMC1A is primary rather than secondary. Few studies report ophthalmologic findings specific to SMC1A. Based on these findings, LVNC cardiomyopathy and cleft lip should be considered features of SMC1A-associated CdLS. All patients should receive echocardiogram and undergo thorough ophthalmologic evaluation as part of routine CdLS care. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Fenda Labial/genética , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Cardiopatias Congênitas/genética , Fenótipo , Transtornos da Visão/genética , Fenda Labial/diagnóstico , Ecocardiografia , Facies , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Transtornos da Visão/diagnóstico
6.
Pediatrics ; 135(3): e736-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25687148

RESUMO

Single-nucleotide polymorphism arrays and other types of genetic tests have the potential to detect first-degree consanguinity and uncover parental rape in cases of minor teenage pregnancy. We present 2 cases in which genetic testing identified parental rape of a minor teenager. In case 1, single-nucleotide polymorphism array in a patient with multiple developmental abnormalities demonstrated multiple long stretches of homozygosity, revealing parental rape of a teenage mother. In case 2, a vague maternal sexual assault history and diagnosis of Pompe disease by direct gene sequencing identified parental rape of a minor. Given the medical, legal, and ethical implications of such revelations, a protocol was developed at our institution to manage consanguinity identified via genetic testing.


Assuntos
Anormalidades Múltiplas/diagnóstico , Consanguinidade , Testes Genéticos/métodos , Anormalidades Múltiplas/genética , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez
7.
Eur J Hum Genet ; 23(6): 761-5, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25271087

RESUMO

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.


Assuntos
Proteínas Argonauta/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Deficiências do Desenvolvimento/genética , Fatores de Iniciação em Eucariotos/genética , Hipotonia Muscular/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Feminino , Haploinsuficiência , Humanos , Masculino , Hipotonia Muscular/diagnóstico , Síndrome
8.
Genet Med ; 17(5): 400-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25232848

RESUMO

PURPOSE: The broad use of single-nucleotide polymorphism microarrays has increased identification of unexpected consanguinity. Therefore, guidelines to address reporting of consanguinity have been published for clinical laboratories. Because no such guidelines for clinicians exist, we describe a case and present recommendations for clinicians to disclose unexpected consanguinity to families. METHODS: In a boy with multiple endocrine abnormalities and structural birth defects, single-nucleotide polymorphism array analysis revealed ~23% autosomal homozygosity suggestive of a first-degree parental relationship. We assembled an interdisciplinary health-care team, planned the most appropriate way to discuss results of the single-nucleotide polymorphism array with the adult mother, including the possibility of multiple autosomal recessive disorders in her child, and finally met with her as a team. RESULTS: From these discussions, we developed four major considerations for clinicians returning results of unexpected consanguinity, all guided by the child's best interests: (i) ethical and legal obligations for reporting possible abuse, (ii) preservation of the clinical relationship, (iii) attention to justice and psychosocial challenges, and (iv) utilization of the single-nucleotide polymorphism array results to guide further testing. CONCLUSION: As single-nucleotide polymorphism arrays become a common clinical diagnostic tool, clinicians can use this framework to return results of unexpected consanguinity to families in a supportive and productive manner.


Assuntos
Consanguinidade , Achados Incidentais , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Família , Homozigoto , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Médicos , Revelação da Verdade
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