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1.
Am J Hum Genet ; 108(1): 134-147, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33340455

RESUMO

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.


Assuntos
Epilepsia/genética , Hipotireoidismo/genética , Transtornos do Neurodesenvolvimento/genética , Receptores Notch/genética , Transdução de Sinais/genética , Ubiquitina-Proteína Ligases/genética , Animais , Anus Imperfurado/genética , Caenorhabditis elegans/genética , Linhagem Celular , Displasia Ectodérmica/genética , Transtornos do Crescimento/genética , Células HEK293 , Perda Auditiva Neurossensorial/genética , Histonas/genética , Humanos , Deficiência Intelectual/genética , Camundongos , Mutação/genética , Nariz/anormalidades , Pancreatopatias/genética , Complexo de Endopeptidases do Proteassoma/genética
2.
J Clin Invest ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001864

RESUMO

BACKGROUND: Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS: One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) clinical site from 2014-2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS: The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSION: For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.

3.
Lancet ; 396(10252): 684-692, 2020 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891212

RESUMO

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.


Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Osteogênese , Absorciometria de Fóton , Acondroplasia/sangue , Adolescente , Biomarcadores/sangue , Estatura , Densidade Óssea , Criança , Pré-Escolar , Colágeno Tipo X/sangue , Método Duplo-Cego , Feminino , Humanos , Reação no Local da Injeção , Injeções Subcutâneas , Masculino , Peptídeo Natriurético Tipo C/uso terapêutico
4.
Am J Med Genet A ; 182(11): 2751-2754, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32885560

RESUMO

Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In this report, we describe a non-Amish, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Initial testing showed that she had a 46,XY chromosome complement, and chromosomal microarray showed a significant absence of heterozygosity (AOH) totalling roughly 600 Mb across multiple different chromosomes, indicating consanguinity. Further workup with exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52) consistent with a diagnosis of SIDDT, explaining many of her clinical features. However, she was also noted to have a mild T-cell lymphopenia and developed intractable epilepsy after hospital discharge. These features have not previously been reported in SIDDT and may represent phenotypic expansion. To our knowledge, this patient is the 22nd case of SIDDT to be reported in the literature, and the first to be of non-Amish heritage.

5.
Genet Med ; 22(10): 1633-1641, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32576985

RESUMO

PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort. METHODS: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders. RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses. CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.

6.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415109

RESUMO

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Assuntos
Cinesina/genética , Atividade Motora , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Axônios/metabolismo , Movimento Celular , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/metabolismo , Tamanho do Órgão , Organogênese/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética
7.
Genomics ; 112(5): 2937-2941, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32387503

RESUMO

To further assess the scale and level of parental somatic mosaicism, we queried the CMA database at Baylor Genetics. We selected 50 unrelated families where clinically relevant apparent de novo CNV-deletions were found in the affected probands. Parental blood samples screening using deletion junction-specific PCR revealed four parents with somatic mosaicism. Droplet digital PCR (ddPCR), qPCR, and amplicon-based next-generation sequencing (NGS) were applied to validate these findings. Using ddPCR levels of mosaicism ranged from undetectable to 18.5%. Amplicon-based NGS and qPCR for the father with undetectable mosaicism was able to detect mosaicism at 0.39%. In one mother, ddPCR analysis revealed 15.6%, 10.6%, 8.2%, and undetectable levels of mosaicism in her blood, buccal cells, saliva, and urine samples, respectively. Our data suggest that more sensitive and precise methods, e.g. CNV junction-specific LR-PCR, ddPCR, or qPCR may allow for a more refined assessment of the potential disease recurrence risk for an identified variant.

8.
Am J Hum Genet ; 106(5): 717-725, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32330417

RESUMO

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.


Assuntos
Encefalopatias/genética , Quinases Ciclina-Dependentes/genética , Epilepsia Generalizada/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adulto , Sequência de Aminoácidos , Animais , Pré-Escolar , Quinase 8 Dependente de Ciclina/deficiência , Quinase 8 Dependente de Ciclina/genética , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Junção Neuromuscular , Doenças Raras/genética , Convulsões/genética , Síndrome , Adulto Jovem
9.
Hum Mutat ; 41(5): 921-925, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31999386

RESUMO

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.

10.
Am J Med Genet A ; 182(1): 189-194, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633297

RESUMO

Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by congenital lymphedema, intestinal lymphangiectasia, facial dysmorphism, and variable intellectual disability. Known disease genes include CCBE1, FAT4, and ADAMTS3. In a patient with clinically diagnosed Hennekam syndrome but without mutations or copy-number changes in the three known disease genes, we identified a homozygous single-exon deletion affecting FBXL7. Specifically, exon 3, which encodes the F-box domain and several leucine-rich repeats of FBXL7, is eliminated. Our analyses of databases representing >100,000 control individuals failed to identify biallelic loss-of-function variants in FBXL7. Published studies in Drosophila indicate Fbxl7 interacts with Fat, of which human FAT4 is an ortholog, and mutation of either gene yields similar morphological consequences. These data suggest that FBXL7 may be the fourth gene for Hennekam syndrome, acting via a shared pathway with FAT4.

11.
Am J Med Genet A ; 182(1): 224-228, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729153

RESUMO

Agenesis of the corpus callosum is a congenital brain malformation that can occur in isolation or as a component of a congenital syndrome. Hepatoblastoma (HB) is a rare tumor that comprises two thirds of primary hepatic neoplasms in children and adolescents. Up to 20% of children with HB have associated congenital anomalies. In addition to defined genetic syndromes such as Familial Adenomatous Polyposis, Beckwith-Wiedemann syndrome, Trisomy 13, and Trisomy 18, HB is significantly associated with kidney/bladder abnormalities. We present two children with multiple congenital anomalies, including agenesis of the corpus callosum, who were subsequently diagnosed with HB. Review of the literature revealed two patients with clinically-diagnosed Aicardi syndrome and HB. Due to the rarity of both agenesis of the corpus callosum and HB, this is likely a true association. Further investigation into the underlying genetic and molecular basis of this probable association is warranted.

12.
Orphanet J Rare Dis ; 14(1): 232, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640736

RESUMO

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 - 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain. RESULTS: A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events. CONCLUSIONS: This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies. TRIAL REGISTRATION: NCT00348933 . Registered 6 July 2006.


Assuntos
Síndrome de Angelman/tratamento farmacológico , Betaína/uso terapêutico , Ácido Fólico/uso terapêutico , Betaína/administração & dosagem , Criança , Método Duplo-Cego , Ácido Fólico/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Deleção de Sequência , Gêmeos Monozigóticos , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/uso terapêutico
13.
Am J Med Genet A ; 179(10): 2056-2066, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407851

RESUMO

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.


Assuntos
Alelos , Osso e Ossos/anormalidades , Proteínas de Ciclo Celular/genética , Ciclo Celular/genética , Nanismo/genética , Microcefalia/genética , Proteínas Nucleares/genética , Criança , Pré-Escolar , Nanismo/complicações , Família , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/complicações , Linhagem , Fenótipo
14.
Mol Genet Genomic Med ; 7(9): e844, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31350823

RESUMO

BACKGROUND: Geleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF-ß signaling. GPHYSD can be caused by mutations in FBN1, ADAMTLS2, and LTBP3 genes. METHODS AND RESULTS: Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying FBN1 mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying FBN1 mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF-ß signaling did not reduce the storage but improved the extracellular deposition of fibrillin-1 microfibrils. CONCLUSION: Losartan is a promising candidate drug for treatment of GPHYSD due to FBN1 defects.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Fibrilina-1/genética , Fibroblastos/metabolismo , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/metabolismo , Losartan/farmacologia , Lisossomos/metabolismo , Microfibrilas/metabolismo , Pele/metabolismo , Pele/patologia , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Matriz Extracelular , Feminino , Fibroblastos/ultraestrutura , Humanos , Lactente , Deformidades Congênitas dos Membros/patologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
15.
N Engl J Med ; 381(1): 25-35, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31269546

RESUMO

BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).


Assuntos
Acondroplasia/tratamento farmacológico , Crescimento/efeitos dos fármacos , Peptídeo Natriurético Tipo C/análogos & derivados , Osteogênese/efeitos dos fármacos , Acondroplasia/fisiopatologia , Adolescente , Biomarcadores/análise , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Colágeno/sangue , GMP Cíclico/urina , Relação Dose-Resposta a Droga , Feminino , Gráficos de Crescimento , Humanos , Injeções Subcutâneas , Masculino , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/efeitos adversos , Peptídeo Natriurético Tipo C/uso terapêutico
16.
Genome Med ; 11(1): 30, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101064

RESUMO

BACKGROUND: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES. METHODS: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array. RESULTS: The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities. CONCLUSIONS: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.


Assuntos
Variações do Número de Cópias de DNA , Testes Genéticos/métodos , Análise em Microsséries/métodos , Sequenciamento Completo do Exoma/métodos , Aberrações Cromossômicas , Feminino , Testes Genéticos/normas , Homozigoto , Humanos , Limite de Detecção , Masculino , Análise em Microsséries/normas , Sequenciamento Completo do Exoma/normas
17.
Hum Mutat ; 40(7): 908-925, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30817854

RESUMO

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Uridina Difosfato Galactose/metabolismo , Animais , Biópsia , Células CHO , Células Cultivadas , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Cricetulus , Feminino , Humanos , Masculino , Mutação
18.
Eur J Med Genet ; 62(6): 103531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30142436

RESUMO

Interstitial deletions involving chromosome region 6p21.31p21.2 have not been previously reported in the literature. Here, we present a 2 year old girl with global developmental delay, severe speech delay, dysmorphic features, laryngeal cleft, anterior descending aorta that occluded the left main bronchus and a novel de novo deletion of chromosome 6: arr[hg19] 6p21.31p21.2 (35462950-36725083)x1. The deletion, which was diagnosed by array comparative genomic hybridization and further confirmed with fluorescence in situ hybridization, was approximately 1.26 Mb and contained 28 RefSeq genes. The deleted region includes 24 protein coding genes and 4 non-coding genes. This represents a novel microdeletion that has not been previously reported in the literature.


Assuntos
Aorta Torácica/anormalidades , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 6/genética , Anormalidades Congênitas/genética , Deficiências do Desenvolvimento/genética , Laringe/anormalidades , Pré-Escolar , Transtornos Cromossômicos/patologia , Anormalidades Congênitas/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Laringe/patologia , Síndrome
19.
Genet Med ; 21(7): 1652-1656, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30568308

RESUMO

PURPOSE: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci. METHODS: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing. RESULTS: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype. CONCLUSION: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Leucoencefalopatias/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/genética
20.
Am J Med Genet A ; 179(3): 475-479, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569621

RESUMO

Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3-year-old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non-hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast-derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.


Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/diagnóstico , Megalencefalia/genética , Mutação , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Serina-Treonina Quinases TOR/genética , Alelos , Substituição de Aminoácidos , Pré-Escolar , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Mosaicismo , Fenótipo , Polimorfismo de Nucleotídeo Único
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