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2.
Int J Pediatr Otorhinolaryngol ; 151: 110869, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34537546

RESUMO

OBJECTIVES: Head and neck lymphatic malformations (HNLM) are caused by gain-of-function somatic mutations in PIK3CA. Acetylsalicylic acid (ASA/aspirin) is thought to limit growth in PIK3CA-mutated neoplasms through PI3K pathway suppression. We sought to determine if ASA could be beneficial for HNLM. METHODS: Retrospective case series of patients (0-18 years) offered ASA (3-5 mg/kg/day) for HNLM treatment (2010-2018). Clinical and treatment characteristics, patient-reported symptom improvement, medication tolerance, compliance, and complications were recorded. Treatment response was determined by change in patient/caregiver-reported symptoms, or HNLM size [complete (resolved), partial (decreased), or stable]. RESULTS: Fifty-three patients were offered ASA, 23 (43%) accepted (median age 10 years, IQR 6-14). Compared to patients who declined, patients receiving ASA were more likely to have extensive malformations: ex-utero intrapartum treatment procedure, bilateral malformations, oral cavity location, ≥2 invasive treatments, or tracheotomy (p < 0.05). All patients with tissue available had PIK3CA mutations (13/23). Treatment indications included oral pain/blebs (12, 52%), recurrent pain/swelling (6, 26%), or sudden/persistent swelling (5, 22%). Treatment plan was commonly one 81 mg tablet daily (19, 83%) for 3-12 months (8, 42%). Therapeutic adherence was reported by 18 patients (78%). Symptoms improved in 18 patients [78%; decreased pain (9, 39%) and swelling (8, 35%)]. Treatment resulted in partial (14, 61%) or complete response (4, 17%). Three patients developed oral bleb bleeding, which resolved with medication discontinuation. CONCLUSION: ASA seems to be a well-tolerated, low-risk medication for HNLM treatment. This pilot study suggests that it often improves symptoms and reduces HNLM size. Further prospective, randomized studies are warranted to comprehensively assess indications, safety, and efficacy. LEVEL OF EVIDENCE: Level 4.

3.
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
4.
Am J Hum Genet ; 108(1): 8-15, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417889

RESUMO

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genômica/métodos , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Humanos , Mutação/genética , Fenótipo
5.
Genet Med ; 23(1): 123-130, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32884133

RESUMO

PURPOSE: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM. METHODS: cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital polymerase chain reaction (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay. RESULTS: Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5). CONCLUSION: Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients, which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.


Assuntos
Ácidos Nucleicos Livres , Malformações Vasculares , Ácidos Nucleicos Livres/genética , Humanos , Reação em Cadeia da Polimerase Multiplex , Mutação , Estudos Prospectivos , Malformações Vasculares/diagnóstico , Malformações Vasculares/genética
6.
Am J Med Genet A ; 185(1): 213-218, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044030

RESUMO

Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.

7.
Am J Med Genet A ; 185(3): 827-835, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33296147

RESUMO

CHRNB1 encodes the ß subunit of the acetylcholine receptor (AChR) at the neuromuscular junction. Inherited defects in the neuromuscular junction can lead to congenital myasthenia syndrome (CMS), a clinically and genetically heterogeneous group of disorders which includes fetal akinesia deformation sequence (FADS) on the severe end of the spectrum. Here, we report two unrelated families with biallelic CHRNB1 variants, and in each family, one child presented with lethal FADS. We contrast the diagnostic odysseys in the two families, one of which lasted 16 years while the other, utilizing rapid exome sequencing, led to specific treatment in the first 2 weeks of life. Furthermore, we note that CHRNB1 variants may be under-recognized because in both families, one of the variants is a single exon deletion that has been previously described but may not easily be detected in clinically available genetic testing.

8.
J Pediatr ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32553838

RESUMO

OBJECTIVES: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population. STUDY DESIGN: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES. RESULTS: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days. CONCLUSIONS: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.

9.
Hum Mol Genet ; 29(2): 320-334, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31915823

RESUMO

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Complexo 4 de Proteínas Adaptadoras/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico/genética , Paraplegia Espástica Hereditária/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Rede trans-Golgi/metabolismo , Complexo 4 de Proteínas Adaptadoras/deficiência , Subunidades beta do Complexo de Proteínas Adaptadoras/metabolismo , Adolescente , Autofagossomos/metabolismo , Autofagia/genética , Linhagem Celular , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Ferro/metabolismo , Mutação com Perda de Função , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Neurogênese/genética , Neurônios/metabolismo , Paraplegia Espástica Hereditária/genética , Rede trans-Golgi/genética
10.
Am J Med Genet A ; 182(3): 543-547, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31814264

RESUMO

We describe a 5-year-old male with developmental delay, behavioral problems, and dysmorphic features who was found by microarray to have a 93-kb duplication of uncertain significance that fully encompasses the third exon of CTNND2 (delta catenin). Mate-pair sequencing was used to determine that the duplication is tandem and is predicted to lead to CTNND2 haploinsufficiency. Haploinsufficiency for CTNND2 has been shown to result in developmental delay and intellectual disability, providing a unifying diagnosis for this patient. His features overlap those associated with the larger cri-du-chat deletion of this region, expanding the clinical phenotype of isolated CTNND2 variants. The use of mate-pair sequencing to determine the orientation of the small duplication was essential to the diagnosis and avoided the use of exome sequencing, which would not have defined the arrangement of the duplication. This is only the second reported patient, to our knowledge, with a single exon duplication of CTNND2.


Assuntos
Anormalidades Múltiplas/genética , Transtorno Autístico/genética , Cateninas/genética , Predisposição Genética para Doença , Atrofia Muscular/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/patologia , Criança , Pré-Escolar , Éxons/genética , Facies , Feminino , Genes Duplicados/genética , Haploinsuficiência/genética , Humanos , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/patologia , Linhagem , Comportamento Problema
11.
Hum Mutat ; 41(1): 299-315, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595648

RESUMO

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.


Assuntos
Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromina 1/genética , Substituição de Aminoácidos , Estudos Transversais , Heterozigoto , Humanos , Fenótipo
12.
Am J Hum Genet ; 105(3): 606-615, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474318

RESUMO

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.


Assuntos
Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Masculino , Gravidez
13.
JCI Insight ; 4(21)2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536475

RESUMO

Lymphatic malformations (LMs) are congenital, nonneoplastic vascular malformations associated with postzygotic activating PIK3CA mutations. The mutation spectrum within LMs is narrow, with the majority having 1 of 3 hotspot mutations. Despite this relative genetic homogeneity, clinical presentations differ dramatically. We used molecular inversion probes and droplet digital polymerase chain reaction to perform deep, targeted sequencing of PIK3CA in 271 affected and unaffected tissue samples from 81 individuals with isolated LMs and retrospectively collected clinical data. Pathogenic PIK3CA mutations were identified in affected LM tissue in 64 individuals (79%) with isolated LMs, with variant allele fractions (VAFs) ranging from 0.1% to 13%. Initial analyses revealed no correlation between VAF and phenotype variables. Recognizing that different mutations activate PI3K to varying degrees, we developed a metric, the genotype-adjusted VAF (GVAF), to account for differences in mutation strength, and found significantly higher GVAFs in LMs with more severe clinical characteristics including orofacial location or microcystic structure. In addition to providing insight into LM pathogenesis, we believe GVAF may have broad applicability for genotype-phenotype analyses in mosaic disorders.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Genótipo , Vasos Linfáticos/anormalidades , Mutação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Vasos Linfáticos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Am J Hum Genet ; 104(5): 936-947, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982608

RESUMO

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.


Assuntos
Anormalidades Congênitas/etiologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Microglia/patologia , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Animais , Criança , Anormalidades Congênitas/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Homozigoto , Humanos , Lactente , Recém-Nascido , Microglia/metabolismo , Linhagem , Fenótipo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto Jovem , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
J Genet Couns ; 28(2): 283-291, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30964580

RESUMO

Exome sequencing (ES) has revolutionized molecular diagnosis in children with genetic disease over the past decade. However, exome sequencing in the inpatient setting has traditionally been discouraged, in part due to an increased risk of providers failing to retrieve and act upon results, as many patients are discharged before results return. The development of rapid turn-around-times (TATs) for genomic testing has begun to shift this paradigm. Rapid exome sequencing (rES) is increasingly being used as a diagnostic tool for critically ill infants with likely genetic disease and presents significant challenges to execute. We implemented a program, entitled the Rapid Inpatient Genomic Testing (RIGhT) project, to identify critically ill children for whom a molecular diagnosis is likely to change inpatient management. Two important goals of the RIGhT project were to provide appropriate genetic counseling, and to develop protocols to ensure efficient test coordination- both of which relied heavily on laboratory and clinic-based genetic counselors (GCs). Here, rES was performed on 27 inpatient trios from October 2016 to August 2018; laboratory and clinical GCs encountered significant challenges in the coordination of this testing. The GCs involved retrospectively reviewed these cases and identified three common challenges encountered during pretest counseling and coordination. The aim of this paper is to define these challenges using illustrative case examples that highlight the importance of including GCs to support rES programs.


Assuntos
Conselheiros , Aconselhamento Genético , Testes Genéticos , Unidades de Terapia Intensiva Pediátrica , Sequenciamento Completo do Exoma , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
16.
Am J Med Genet A ; 179(5): 842-845, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30828993

RESUMO

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.


Assuntos
Células Acinares/metabolismo , Exoma , Pneumopatias/diagnóstico , Pneumopatias/genética , Deleção de Sequência , Proteínas com Domínio T/genética , Sequenciamento Completo do Exoma , Biópsia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino
17.
Am J Med Genet C Semin Med Genet ; 178(3): 374-378, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30260069

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by hamartomatous growths in the brain, kidneys, lungs, skin, heart, and retina. TSC is caused by loss of function mutations in one of two tumor suppressor genes, TSC1 or TSC2. Two-thirds of individuals with TSC have de novo mutations, and individuals with postzygotic pathogenic variants in both TSC1 and TSC2 have been reported. The development of sensitive molecular methods, such as next generation sequencing, has led to an increased ability to detect low-level mosaic variants, which are typically thought to have milder phenotypes because a smaller fraction of cells in the body harbor the mutation. Here, we describe two patients with TSC who had severe phenotypic involvement, but only low-level mosaicism in TSC2. Given this apparent discrepancy and concern about a missed constitutional variant, we sampled multiple tissues in both cases to confirm these mosaic mutations. Sampling of multiple tissues can be crucial in molecular diagnosis of mosaic TSC. These cases highlight, in general, challenges in molecular diagnosis of genetic conditions due to postzygotic mutations.


Assuntos
Encéfalo/diagnóstico por imagem , Mosaicismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/etiologia , Adolescente , Encéfalo/anormalidades , Encéfalo/patologia , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Linhagem
18.
Am J Med Genet A ; 176(11): 2301-2308, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30063105

RESUMO

PIK3CA-related overgrowth spectrum (PROS) refers to a group of disorders of segmental overgrowth of a wide variety of tissues as well as venous and lymphatic malformations. Clinical and molecular diagnosis can be challenging due to phenotypic heterogeneity and difficulties detecting low-level mosaicism using standard methods. Here, we report a patient with a severe presentation of PIK3CA-related overgrowth with analysis of 27 posthumously collected tissues by droplet digital polymerase chain reaction (PCR) at autopsy. This patient had a complicated medical course, with coagulopathy, ischemic brain injury, and sepsis resulting in multi-organ failure and death at age 2 months despite sirolimus therapy. Five of the 27 tissues analyzed possessed a mosaic PIK3CA mutation (p.E545K), with mutation levels ranging from 3 to 20% across affected tissues. We found no correlation between tissue-specific disease severity and mutation levels, likely reflecting sampling limitations. We also tested a series of 22 individuals with somatic overgrowth and/or vascular-lymphatic malformations using a targeted next generation sequencing panel and found PIK3CA mutations in nine individuals, identifying three novel PIK3CA variants. This report expands the clinical and molecular spectrum of PROS, emphasizes that different molecular methods can be complimentary in the diagnosis of these disorders, and highlights the risk of coagulopathy in a subset of patients with PIK3CA-related overgrowth.


Assuntos
Anormalidades Múltiplas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Relatório de Pesquisa , Alelos , Autopsia , Estudos de Coortes , Humanos , Malformações Vasculares/genética
19.
Childs Nerv Syst ; 34(11): 2155-2171, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30078055

RESUMO

PURPOSE: To provide the reader with a comprehensive but concise understanding of congenital scoliosis METHODS: We have undertaken to summarize available literature on the pathophysiology, epidemiology, and management of congenital scoliosis. RESULTS: Congenital scoliosis represents 10% of pediatric spine deformity and is a developmental error in segmentation, formation, or a combination of both leading to curvature of the spine. Treatment options are complicated by balancing growth potential with curve severity. Often associated abnormalities of cardiac, genitourinary, or intraspinal systems are concurrent and should be evaluated as part of the diagnostic work-up. Management balances the risk of progression, growth potential, lung development/function, and associated risks. Surgical treatment options involve growth-permitting systems or fusions. CONCLUSION: Congenital scoliosis is a complex spinal problem associated with many other anomalous findings. Treatment options are diverse but enable optimization of management and care of these children.


Assuntos
Escoliose/congênito , Escoliose/diagnóstico , Escoliose/terapia , Feminino , Humanos , Masculino
20.
Genet Med ; 20(11): 1354-1364, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29671837

RESUMO

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia. METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort. RESULTS: The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria. CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.


Assuntos
Encéfalo/diagnóstico por imagem , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico , Lisencefalia/diagnóstico , Sequenciamento Completo do Exoma , Encéfalo/fisiopatologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico por imagem , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lisencefalia/diagnóstico por imagem , Lisencefalia/genética , Lisencefalia/fisiopatologia , Masculino , Mutação/genética
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