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1.
J Med Genet ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675124

RESUMO

BACKGROUND: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. METHODS: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. RESULTS: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. CONCLUSION: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

2.
Elife ; 102021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34387191

RESUMO

Cytoplasmic lipid droplets are highly dynamic storage organelles that are critical for cellular lipid homeostasis. While the molecular details of lipid droplet dynamics are a very active area of investigation, this work has been primarily performed in cultured cells. Taking advantage of the powerful transgenic and in vivo imaging opportunities available in zebrafish, we built a suite of tools to study lipid droplets in real time from the subcellular to the whole organism level. Fluorescently tagging the lipid droplet-associated proteins, perilipin 2 and perilipin 3, in the endogenous loci permits visualization of lipid droplets in the intestine, liver, and adipose tissue. Using these tools, we found that perilipin 3 is rapidly loaded on intestinal lipid droplets following a high-fat meal and later replaced by perilipin 2. These powerful new tools will facilitate studies on the role of lipid droplets in different tissues, under different genetic and physiological manipulations, and in a variety of human disease models.


Assuntos
Adipócitos/metabolismo , Gotículas Lipídicas/metabolismo , Perilipina-2/metabolismo , Perilipina-3/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Tecido Adiposo/metabolismo , Animais , Animais Geneticamente Modificados , Homeostase , Metabolismo dos Lipídeos , Perilipina-2/genética , Perilipina-3/genética , Peixe-Zebra/metabolismo
3.
Hum Genet ; 140(8): 1229-1239, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34159400

RESUMO

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.


Assuntos
Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , Mutação , Fatores de Transcrição/genética , Enzimas Ativadoras de Ubiquitina/genética , Sequência de Bases , Estudos de Coortes , Variações do Número de Cópias de DNA , Expressão Gênica , Testes Genéticos , Humanos , Lactente , Deformidades Congênitas dos Membros/metabolismo , Deformidades Congênitas dos Membros/patologia , Masculino , Linhagem , Fatores de Transcrição/deficiência , Enzimas Ativadoras de Ubiquitina/deficiência , Sequenciamento Completo do Genoma
4.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070208

RESUMO

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat-Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Hirschsprung/imunologia , Deficiência Intelectual/imunologia , Microcefalia/imunologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/imunologia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Facies , Feminino , Perfilação da Expressão Gênica , Haploinsuficiência , Doença de Hirschsprung/genética , Humanos , Imunidade Celular , Memória Imunológica/genética , Deficiência Intelectual/genética , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Mutação , Subpopulações de Linfócitos T/imunologia , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de Zinco/deficiência , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
5.
Sci Rep ; 11(1): 9560, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953269

RESUMO

Tonne-Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome associated with variable clinical features including craniofacial abnormalities, hypogenitalism and diaphragmatic hernia. TOKAS is caused exclusively by variants in the gene encoding the E3 ubiquitin ligase gene RLIM, also known as RNF12. Here we report identification of a novel RLIM missense variant, c.1262A>G p.(Tyr421Cys) adjacent to the regulatory basic region, which causes a severe form of TOKAS resulting in perinatal lethality by diaphragmatic hernia. Inheritance and X-chromosome inactivation patterns implicate RLIM p.(Tyr421Cys) as the likely pathogenic variant in the affected individual and within the kindred. We show that the RLIM p.(Tyr421Cys) variant disrupts both expression and function of the protein in an embryonic stem cell model. RLIM p.(Tyr421Cys) is correctly localised to the nucleus, but is readily degraded by the proteasome. The RLIM p.(Tyr421Cys) variant also displays significantly impaired E3 ubiquitin ligase activity, which interferes with RLIM function in Xist long-non-coding RNA induction that initiates imprinted X-chromosome inactivation. Our data uncover a highly disruptive missense variant in RLIM that causes a severe form of TOKAS, thereby expanding our understanding of the molecular and phenotypic spectrum of disease severity.


Assuntos
Anormalidades Craniofaciais/genética , Hérnia Diafragmática/genética , Hipogonadismo/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Humanos , Recém-Nascido , Masculino , Ubiquitinação
6.
J Mol Diagn ; 23(7): 894-905, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962052

RESUMO

Massively parallel sequencing has markedly improved mendelian diagnostic rates. This study assessed the effects of custom alterations to a diagnostic genomic bioinformatic pipeline in response to clinical need and derived practice recommendations relative to diagnostic rates and efficiency. The Genomic Annotation and Interpretation Application (GAIA) bioinformatics pipeline was designed to detect panel, exome, and genome sample integrity and prioritize gene variants in mendelian disorders. Reanalysis of selected negative cases was performed after improvements to the pipeline. GAIA improvements and their effect on sensitivity are described, including addition of a PubMed search for gene-disease associations not in the Online Mendelian Inheritance of Man database, inclusion of a process for calling low-quality variants (known as QPatch), and gene symbol nomenclature consistency checking. The new pipeline increased the diagnostic rate and reduced staff costs, resulting in a saving of US$844.34 per additional diagnosis. Recommendations for genomic analysis pipeline requirements are summarized. Clinically responsive bioinformatics pipeline improvements increase diagnostic sensitivity and increase cost-effectiveness.

7.
Hum Genet ; 140(7): 1061-1076, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33811546

RESUMO

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.


Assuntos
Anormalidades Múltiplas/genética , Caderinas/genética , Adesão Celular/genética , Anormalidades Craniofaciais/genética , Deformidades Congênitas do Pé/genética , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Hipertelorismo/genética , Sequência de Aminoácidos , Movimento Celular/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo
8.
NPJ Genom Med ; 6(1): 5, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510162

RESUMO

In scaling up an ultra-rapid genomics program, we used implementation science principles to design and investigate influences on implementation and identify strategies required for sustainable "real-world" services. Interviews with key professionals revealed the importance of networks and relationship building, leadership, culture, and the relative advantage afforded by ultra-rapid genomics in the care of critically ill children. Although clinical geneticists focused on intervention characteristics and the fit with patient-centered care, intensivists emphasized the importance of access to knowledge, in particular from clinical geneticists. The relative advantage of ultra-rapid genomics and trust in consistent and transparent delivery were significant in creating engagement at initial implementation, with appropriate resourcing highlighted as important for longer term sustainability of implementation. Our findings demonstrate where common approaches can be used and, significantly, where there is a need to tailor support by professional role and implementation phase, to maximize the potential of ultra-rapid genomic testing to improve patient care.

9.
Eur J Hum Genet ; 29(1): 79-87, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32678339

RESUMO

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for gene-phenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement.


Assuntos
Conferências de Consenso como Assunto , Triagem de Portadores Genéticos/métodos , Austrália , Triagem de Portadores Genéticos/estatística & dados numéricos , Predisposição Genética para Doença , Humanos , Locos de Características Quantitativas
10.
PLoS Genet ; 16(8): e1008941, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760060

RESUMO

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.


Assuntos
Proteínas de Transporte/genética , Lipídeos/genética , Lipoproteínas/genética , Triglicerídeos/genética , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Trato Gastrointestinal/metabolismo , Humanos , Imunoprecipitação , Gotículas Lipídicas/metabolismo , Lipoproteínas/metabolismo , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Transporte Proteico/genética , Triglicerídeos/metabolismo , Peixe-Zebra/genética
11.
Genet Med ; 22(12): 1976-1985, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32719395

RESUMO

PURPOSE: To explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children. METHODS: Parents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome Scale. RESULTS: With 96 survey invitations sent, the response rate was 57% (n = 55). Most parents reported receiving enough information during pretest (n = 50, 94%) and post-test (n = 44, 83%) counseling. Perceptions varied regarding benefits of testing, however most parents reported no or mild decision regret (n = 45, 82%). The majority of parents (31/52, 60%) were extremely concerned about the condition recurring in future children, regardless of actual or perceived recurrence risk. Parents whose child received a diagnostic result reported higher empowerment. CONCLUSION: This study provides valuable insight into parental experiences of ultrarapid genomic testing in critically unwell children, including decision regret, empowerment, and post-test reproductive planning, to inform design and delivery of rapid diagnosis programs. The findings suggest considerations for pre- and post-test counseling that may influence parental experiences during the testing process and beyond, such as the importance of realistically conveying the likelihood for clinical and/or personal utility.


Assuntos
Emoções , Pais , Criança , Aconselhamento , Testes Genéticos , Humanos , Lactente , Inquéritos e Questionários
12.
JAMA ; 323(24): 2503-2511, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32573669

RESUMO

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems. Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system. Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption. Exposures: Ultra-rapid exome sequencing. Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge. Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%). Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.


Assuntos
Estado Terminal , Doenças Genéticas Inatas/genética , Testes Genéticos/métodos , Sequenciamento Completo do Exoma/métodos , Austrália , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Programas Nacionais de Saúde , Estudos Prospectivos , Fatores de Tempo
13.
Genet Med ; 22(10): 1623-1632, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32499604

RESUMO

PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.


Assuntos
Anormalidades do Olho , Oftalmopatias Hereditárias , Proteínas ADAMTS , Segmento Anterior do Olho , Citocromo P-450 CYP1B1/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Fatores de Transcrição Forkhead/genética , Humanos , Mutação , Linhagem
14.
Am J Med Genet A ; 182(7): 1576-1591, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32500973

RESUMO

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.


Assuntos
Mesilato de Imatinib/uso terapêutico , Leucoencefalopatias/etiologia , Miofibromatose/congênito , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adolescente , Adulto , Aneurisma/genética , Criança , Feminino , Estudos de Associação Genética , Humanos , Lactente , Leucoencefalopatias/tratamento farmacológico , Leucoencefalopatias/genética , Masculino , Miofibromatose/tratamento farmacológico , Miofibromatose/etiologia , Miofibromatose/genética , Linhagem , Inibidores de Proteínas Quinases/uso terapêutico
15.
Hum Mutat ; 41(8): 1425-1434, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32442335

RESUMO

LARS2 variants are associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss, and with an infantile lethal multisystem disorder: Hydrops, lactic acidosis, sideroblastic anemia (HLASA) in one individual. Recently we reported LARS2 deafness with (ovario) leukodystrophy. Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA-like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy, lactic acidosis, and developmental delay. Three HLASA cases from two unrelated families were identified. All were males with genital anomalies. Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss. A 55-year old male with deafness has not displayed neurological symptoms while his female siblings with Perrault syndrome developed leukodystrophy and died in their 30s. Analysis of muscle from a child with a reversible myopathy showed reduced LARS2 and mitochondrial complex I levels, and an unusual form of degeneration. Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA-associated variants having the most severe effect. A broad phenotypic spectrum should be considered in association with LARS2 variants.


Assuntos
Aminoacil-tRNA Sintetases/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Miopatias Mitocondriais/genética , Acidose Láctica/genética , Adulto , Anemia Sideroblástica/genética , Edema/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Estrutura Terciária de Proteína
17.
Am J Primatol ; 82(11): e23050, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31531899

RESUMO

Attachment theory holds that parental relationships have lifelong effects on offspring social lives. The tend-and-befriend hypothesis posits that female friendships among humans evolved as part of a primate-wide coping mechanism to mediate stress by relying on social support. Here we bridge developmental and evolutionary frameworks to examine adolescent girls' perception of their reliance on female friendship for social support, how perceptions of parental relationships affect peer relationships, and the extent to which parent and peer relationships buffer depressive symptoms. We predict perceived maternal relationship quality will be positively associated with close female friendships, and maternal relationships, paternal relationships, and female friendship will buffer depressive symptoms. Participants were adolescent girls from a summer science camp (N = 95). Participants filled out demographic information, social network surveys, the Parent-Adolescent Communication Scale, and the Center for Epidemiology Depression Scale. Data was analyzed with Pearson's correlations, t tests, and path analysis. Adolescent girls with few female friends, compared with girls who had more than two very close female friends, experienced more depressive symptoms (t = 3.382, p = .001, D = 0.784). Adolescent girls with few female friends experienced more depressive symptoms compared to girls with two or more very close female friends (t = 3.382, p = .001, D = 0.784). Stronger maternal and paternal relationships were associated with having more female friends (maternal: t = -3.213, p = .003, D = 0.837; paternal: t = -2.432; p = .017). In the path analysis model, only maternal relationship quality significantly predicted female friendship category (ß = .33, CR = 2.770, p < .006). Furthermore, participants with two or more very close female friends and higher paternal relationship quality had significantly fewer depressive symptoms (friends; ß = -.19, CR = -2.112, p = .035; paternal: ß = -.33, CR = -3.220, p < .001), and older participants had more depressive symptoms (ß = .17, CR = -1.931, p = .036). These results provide additional support for the tend-and-befriend hypothesis, suggesting that maternal tending sets the stage for close female friendships.


Assuntos
Depressão/epidemiologia , Amigos/psicologia , Relações Pais-Filho , Apoio Social , Adolescente , Feminino , Humanos , Relações Interpessoais , Apego ao Objeto , Psicologia do Adolescente
18.
J Clin Med ; 8(11)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752325

RESUMO

PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

19.
Genet Med ; 21(5): 1111-1120, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30293987

RESUMO

PURPOSE: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. METHODS: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. RESULTS: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. CONCLUSIONS: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.


Assuntos
Testes Genéticos/métodos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Sequência de Bases/genética , Mapeamento Cromossômico/métodos , Estudos de Coortes , Exoma/genética , Família , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação/genética , Pais , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
20.
Nat Genet ; 50(10): 1442-1451, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224647

RESUMO

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Histonas/metabolismo , Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Acetilação , Adolescente , Animais , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona , Estudos de Coortes , Proteínas de Ligação a DNA , Feminino , Genes Ligados ao Cromossomo X , Células HEK293 , Histona Acetiltransferases/metabolismo , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Transtornos do Neurodesenvolvimento/metabolismo , Processamento de Proteína Pós-Traducional/genética , Síndrome
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