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1.
Genet Med ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33173220

RESUMO

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

2.
Genet Med ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33144682

RESUMO

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

4.
Mol Genet Genomic Med ; 8(9): e1341, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32597037

RESUMO

BACKGROUND: RNA polymerase III (Pol III)-related disorders are autosomal recessive neurodegenerative disorders caused by variants in POLR3A or POLR3B. Recently, a novel phenotype of adult-onset spastic ataxia was identified in individuals with the c.1909+22G>A POLR3A variant in compound heterozygosity. METHODS: Whole-exome sequencing was performed in the proband and parents. Variants were confirmed by Sanger sequencing. RNA sequencing was performed to evaluate splicing implications. RESULTS: A 42-year-old female was evaluated for unexplained neurological findings with a slow progressive decline in gait and walking speed since adolescence. WES revealed a novel missense variant (c.3593A>C, p.Lys1198Arg) in exon 27 of POLR3A in compound heterozygosity with the c.1909+22G>A variant. Summary of previously reported clinical features from individuals with pathogenic biallelic alterations in POLR3A and adult-onset phenotype is consistent with our findings. RNA analysis revealed c.3593A>G drives the production of four RNA transcript products each with different functional impacts. CONCLUSION: The novel dual-class c.3593A>C variant in POLR3A causes an amino acid substitution and complex disruption of splicing. Our report supports the need to investigate variants near splice junctions for proper interpretation. Current interpretation guidelines need to address best practices for inclusion of predicted or measured transcriptional disruption pending functional activity or reliable transcript abundance estimates.

5.
Bioinformatics ; 36(17): 4609-4615, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315392

RESUMO

MOTIVATION: Next-generation sequencing is rapidly improving diagnostic rates in rare Mendelian diseases, but even with whole genome or whole exome sequencing, the majority of cases remain unsolved. Increasingly, RNA sequencing is being used to solve many cases that evade diagnosis through sequencing alone. Specifically, the detection of aberrant splicing in many rare disease patients suggests that identifying RNA splicing outliers is particularly useful for determining causal Mendelian disease genes. However, there is as yet a paucity of statistical methodologies to detect splicing outliers. RESULTS: We developed LeafCutterMD, a new statistical framework that significantly improves the previously published LeafCutter in the context of detecting outlier splicing events. Through simulations and analysis of real patient data, we demonstrate that LeafCutterMD has better power than the state-of-the-art methodology while controlling false-positive rates. When applied to a cohort of disease-affected probands from the Mayo Clinic Center for Individualized Medicine, LeafCutterMD recovered all aberrantly spliced genes that had previously been identified by manual curation efforts. AVAILABILITY AND IMPLEMENTATION: The source code for this method is available under the opensource Apache 2.0 license in the latest release of the LeafCutter software package available online at http://davidaknowles.github.io/leafcutter. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

6.
Eur J Hum Genet ; 28(6): 770-782, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32005960

RESUMO

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

7.
PLoS One ; 14(10): e0223337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31577830

RESUMO

BACKGROUND: RNA sequencing has been proposed as a means of increasing diagnostic rates in studies of undiagnosed rare inherited disease. Recent studies have reported diagnostic improvements in the range of 7.5-35% by profiling splicing, gene expression quantification and allele specific expression. To-date however, no study has systematically assessed the presence of gene-fusion transcripts in cases of germline disease. Fusion transcripts are routinely identified in cancer studies and are increasingly recognized as having diagnostic, prognostic or therapeutic relevance. Isolated reports exist of fusion transcripts being detected in cases of developmental and neurological phenotypes, and thus, systematic application of fusion detection to germline conditions may further increase diagnostic rates. However, current fusion detection methods are unsuited to the investigation of germline disease due to performance biases arising from their development using tumor, cell-line or in-silico data. METHODS: We describe a tailored approach to fusion candidate identification and prioritization in a cohort of 47 undiagnosed, suspected inherited disease patients. We modify an existing fusion transcript detection algorithm by eliminating its cell line-derived filtering steps, and instead, prioritize candidates using a custom workflow that integrates genomic and transcriptomic sequence alignment, biological and technical annotations, customized categorization logic, and phenotypic prioritization. RESULTS: We demonstrate that our approach to fusion transcript identification and prioritization detects genuine fusion events excluded by standard analyses and efficiently removes phenotypically unimportant candidates and false positive events, resulting in a reduced candidate list enriched for events with potential phenotypic relevance. We describe the successful genetic resolution of two previously undiagnosed disease cases through the detection of pathogenic fusion transcripts. Furthermore, we report the experimental validation of five additional cases of fusion transcripts with potential phenotypic relevance. CONCLUSIONS: The approach we describe can be implemented to enable the detection of phenotypically relevant fusion transcripts in studies of rare inherited disease. Fusion transcript detection has the potential to increase diagnostic rates in rare inherited disease and should be included in RNA-based analytical pipelines aimed at genetic diagnosis.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Proteínas Mutantes Quiméricas/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Marcadores Genéticos , Humanos , Lactente , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Fenótipo , Fluxo de Trabalho , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-31662300

RESUMO

Trichorhinophalangeal syndrome type I (TRPSI) is a rare disorder that causes distinctive ectodermal, facial, and skeletal features affecting the hair (tricho-), nose (rhino-), and fingers and toes (phalangeal) and is inherited in an autosomal dominant pattern. TRPSI is caused by loss of function variants in TRPS1, involved in the regulation of chondrocyte and perichondrium development. Pathogenic variants in TRPS1 include missense mutations and deletions with variable breakpoints, with only a single instance of an intragenic duplication reported to date. Here we report an affected individual presenting with a classic TRPSI phenotype who is heterozygous for a de novo intragenic ∼36.3-kbp duplication affecting exons 2-4 of TRPS1 Molecular analysis revealed the duplication to be in direct tandem orientation affecting the splicing of TRPS1 The aberrant transcripts are predicted to produce a truncated TRPS1 missing the nuclear localization signal and the GATA and IKAROS-like zinc-finger domains resulting in functional TRPS1 haploinsufficiency. Our study identifies a novel intragenic tandem duplication of TRPS1 and highlights the importance of molecular characterization of intragenic duplications.


Assuntos
Dedos/anormalidades , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Proteínas Repressoras/genética , Idoso , Criança , Proteínas de Ligação a DNA/genética , Éxons/genética , Família , Feminino , Duplicação Gênica/genética , Doenças do Cabelo/etiologia , Humanos , Síndrome de Langer-Giedion/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Processamento de RNA/genética , Proteínas Repressoras/metabolismo , Deleção de Sequência/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética
9.
Mayo Clin Proc ; 94(9): 1753-1768, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31256854

RESUMO

OBJECTIVE: To demonstrate experience and feasibility of a precision medicine approach for patients with unexplained cytopenias, defined as low blood counts in one or more cell lineages, persistent for 6 months or longer, in the absence of known nutritional, autoimmune, infectious, toxic, and neoplastic (secondary) causes. PATIENTS AND METHODS: Patients were evaluated in our clinic between November 8, 2016, and January 12, 2018. After a thorough evaluation of known causes, family history, and appropriate clinical assays, genomic evaluation was performed in a stepwise manner, through Sanger, targeted, and/or whole-exome sequencing. Variants were analyzed and discussed in a genomics tumor board attended by clinicians, bioinformaticians, and molecular biologists. RESULTS: Sixty-eight patients were evaluated in our clinic. After genomic interrogation, they were classified into inherited bone marrow failure syndromes (IBMFS) (n=24, 35%), cytopenias without a known clinical syndrome which included idiopathic and clonal cytopenias of undetermined significance (CCUS) (n=30, 44%), and patients who did not fit into the above two categories ("others," n=14, 21%). A significant family history was found in only 17 (25%) patients (9 IBMFS, 2 CCUS, and 6 others), whereas gene variants were found in 43 (63%) patients (34 [79%] pathogenic including 12 IBMFS, 17 CCUS, and 5 others]. Genomic assessment resulted in a change in clinical management in 17 (25%) patients, as evidenced by changes in decisions with regards to therapeutic interventions (n=8, 47%), donor choice (n=6, 35%), and/or choice of conditioning regimen for hematopoietic stem cell transplantation (n=8, 47%). CONCLUSION: We show clinical utility of a real-world algorithmic precision medicine approach for unexplained cytopenias.


Assuntos
Contagem de Células Sanguíneas/métodos , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/terapia , Sintomas Inexplicáveis , Medicina de Precisão/métodos , Medicina de Precisão/estatística & dados numéricos , Centros Médicos Acadêmicos , Adolescente , Adulto , Anemia/diagnóstico , Anemia/terapia , Transtornos da Insuficiência da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea/mortalidade , Criança , Estudos de Coortes , Feminino , Genômica , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/terapia , Humanos , Leucopenia/diagnóstico , Leucopenia/terapia , Masculino , Pessoa de Meia-Idade , Neutropenia/diagnóstico , Neutropenia/terapia , Pancitopenia/diagnóstico , Pancitopenia/terapia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Resultado do Tratamento , Adulto Jovem
10.
Am J Hum Genet ; 105(1): 108-121, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31204009

RESUMO

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.


Assuntos
Autofagia , Doenças do Desenvolvimento Ósseo/etiologia , Proteínas de Ciclo Celular/genética , Fibroblastos/patologia , Falência Hepática Aguda/etiologia , Mutação , Idade de Início , Alelos , Sequência de Aminoácidos , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças do Desenvolvimento Ósseo/patologia , Proteínas de Ciclo Celular/metabolismo , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Humanos , Lactente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Linhagem , Transporte Proteico , Recidiva , Homologia de Sequência
11.
Eur J Hum Genet ; 27(8): 1225-1234, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30976111

RESUMO

The DOCK3 gene encodes the Dedicator of cytokinesis 3 (DOCK3) protein, which belongs to the family of guanine nucleotide exchange factors and is expressed almost exclusively in the brain and spinal cord. We used whole exome sequencing (WES) to investigate the molecular cause of developmental delay and hypotonia in three unrelated probands. WES identified truncating and splice site variants in Patient 1 and compound heterozygous and homozygous missense variants in Patients 2 and 3, respectively. We studied the effect of the three missense variants in vitro by using site-directed mutagenesis and pull-down assay and show that the induction of Rac1 activation was significantly lower in DOCK3 mutant cells compared with wild type human DOCK3 (P < 0.05). We generated a protein model to further examine the effect of the two missense variants within or adjacent to the DHR-2 domain in DOCK3 and this model supports pathogenicity. Our results support a loss of function mechanism but the data on the patients with missense variants should be cautiously interpreted because of the variability of the phenotypes and limited number of cases. Prior studies have described DOCK3 bi-allelic loss of function variants in two families with ataxia, hypotonia, and developmental delay. Here, we report on three patients with DOCK3-related developmental delay, wide-based or uncoordinated gait, and hypotonia, further supporting DOCK3's role in a neurodevelopmental syndrome and expanding the spectrum of phenotypic and genotypic variability.


Assuntos
Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Mutação com Perda de Função , Hipotonia Muscular/genética , Proteínas do Tecido Nervoso/genética , Sequenciamento Completo do Exoma/métodos , Criança , Pré-Escolar , Feminino , Genótipo , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Proteínas do Tecido Nervoso/química , Fenótipo
14.
Am J Hum Genet ; 103(5): 666-678, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343943

RESUMO

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.


Assuntos
Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Contratura/genética , Discinesias/genética , Epilepsia/genética , Variação Genética/genética , Megalencefalia/genética , Espasmos Infantis/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/genética
15.
Front Genet ; 9: 276, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090112

RESUMO

Purpose: Demand is increasing for clinical genomic sequencing to provide diagnoses for patients presenting phenotypes indicative of genetic diseases, but for whom routine genetic testing failed to yield a diagnosis. DNA-based testing using high-throughput technologies often identifies variants with insufficient evidence to determine whether they are disease-causal or benign, leading to categorization as variants of uncertain significance (VUS). Methods: We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (SLC2A10). Similar to many disease-relevant membrane proteins, no experimentally derived 3D structure exists. An atomic model was generated and used to evaluate multiple variants, including pathogenic, benign, and VUS. Results: These analyses yielded detailed mechanistic data, not currently predictable from sequence, including altered protein stability, charge distribution of ligand binding surfaces, and shifts toward or away from transport-competent conformations. Consideration of the two major conformations of GLUT10 was important as variants have conformation-specific effects. We generated detailed molecular hypotheses for the functional impact of variants in GLUT10 and propose means to determine their pathogenicity. Conclusion: The type of workflow we present here is valuable for increasing the throughput and resolution with which VUS effects can be assessed and interpreted.

16.
Eur J Hum Genet ; 26(12): 1797-1809, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30097616

RESUMO

Whole exome sequencing (WES) is utilized in diagnostic odyssey cases to identify the underlying genetic cause associated with complex phenotypes. Recent publications suggest that WES reveals the genetic cause in ~25% of these cases and is most successful when applied to children with neurological disease. The residual 75% of cases remain genetically elusive until more information becomes available in the literature or functional studies are pursued. WES performed on three families with presumed ciliopathy diagnoses, including orofaciodigital (OFD) syndrome, fetal encephalocele, or Joubert-related disorder, identified compound heterozygous variants in C2CD3. Biallelic variants in C2CD3 have previously been associated with ciliopathies, including OFD syndrome type 14 (OFD14; MIM: 615948). As three of the six identified variants were predicted to affect splicing, exon-skipping analysis using either RNA sequencing or PCR-based methods were completed to determine the pathogenicity of these variants, and showed that each of the splicing variants led to a frameshifted protein product. Using these studies in combination with the 2015 ACMG guidelines, each of the six identified variants were classified as either pathogenic or likely pathogenic, and are therefore likely responsible for our patients' phenotypes. Each of the families had a distinct clinical phenotype and severity of disease, extending from lethal to viable. These findings highlight that there is a broad phenotypic spectrum associated with C2CD3-mediated disease and not all patients present with the typical features of OFD14.


Assuntos
Ciliopatias/genética , Proteínas Associadas aos Microtúbulos/genética , Síndromes Orofaciodigitais/genética , Fenótipo , Feto Abortado/anormalidades , Adolescente , Adulto , Pré-Escolar , Ciliopatias/patologia , Feminino , Humanos , Lactente , Masculino , Mutação , Síndromes Orofaciodigitais/patologia , Linhagem , Processamento de RNA
17.
Mayo Clin Proc ; 93(7): 834-839, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29976374

RESUMO

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.


Assuntos
Encurtamento do Telômero , Adolescente , Idoso , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Síndrome , Resultado do Tratamento
18.
Artigo em Inglês | MEDLINE | ID: mdl-29802153

RESUMO

Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes EZH2 and NSD1, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for DNMT3A, the co-occurrence of a duplication involving this gene and a pathogenic alteration in EZH2 in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Duplicação Gênica , Deformidades Congênitas da Mão/genética , Anormalidades Múltiplas/patologia , Adulto , Criança , Hipotireoidismo Congênito/patologia , Anormalidades Craniofaciais/patologia , Feminino , Dosagem de Genes , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Linhagem , Fenótipo
19.
J Clin Immunol ; 38(3): 307-319, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29671115

RESUMO

PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. RESULTS: WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. CONCLUSIONS: We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.


Assuntos
Genômica , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/metabolismo , Proteômica , Biomarcadores , Biologia Computacional/métodos , DNA , Feminino , Perfilação da Expressão Gênica , Variação Genética , Genômica/métodos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Imunofenotipagem , Lactente , Proteínas , Proteômica/métodos , RNA , Sequenciamento Completo do Exoma
20.
Am J Hum Genet ; 102(4): 696-705, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29606302

RESUMO

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1-/- mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581∗]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs∗3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.


Assuntos
Alelos , Carboxipeptidases/genética , Colágeno/metabolismo , Tecido Conjuntivo/patologia , Síndrome de Ehlers-Danlos/genética , Mutação/genética , Proteínas Repressoras/genética , Adulto , Sequência de Aminoácidos , Carboxipeptidases/química , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Domínios Proteicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/química , Pele/patologia , Pele/ultraestrutura , Adulto Jovem
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