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1.
Lancet Child Adolesc Health ; 8(4): 301-310, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38485412

RESUMEN

Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of the growing skeleton. In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related FGFR3 conditions, the natural history and impact of achondroplasia over a patient's lifespan, and diagnosis and management options. We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition. These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.


Asunto(s)
Acondroplasia , Niño , Humanos , Acondroplasia/genética , Acondroplasia/terapia
2.
Eur J Hum Genet ; 32(1): 125-129, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37926713

RESUMEN

ATP2B1 encodes plasma membrane calcium-transporting-ATPase1 and plays an essential role in maintaining intracellular calcium homeostasis that regulates diverse signaling pathways. Heterozygous de novo missense and truncating ATP2B1 variants are associated with a neurodevelopmental phenotype of variable expressivity. We describe a proband with distinctive craniofacial gestalt, Pierre-Robin sequence, neurodevelopmental and growth deficit, periventricular heterotopia, brachymesophalangy, cutaneous syndactyly, and persistent hypocalcemia from primary hypoparathyroidism. Proband-parent trio exome sequencing identified compound heterozygous ATP2B1 variants: a maternally inherited splice-site (c.3060+2 T > G) and paternally inherited missense c.2938 G > T; p.(Val980Leu). Reverse-transcription-PCR on the proband's fibroblast-derived mRNA showed aberrantly spliced ATP2B1 transcripts targeted for nonsense-mediated decay. All correctly-spliced ATP2B1 mRNA encoding p.(Val980Leu) functionally causes decreased cellular Ca2+ extrusion. Immunoblotting showed reduced fibroblast ATP2B1. We conclude that biallelic ATP2B1 variants are the likely cause of the proband's phenotype, strengthening the association of ATP2B1 as a neurodevelopmental gene and expanding the phenotypic characterization of a biallelic loss-of-function genotype.


Asunto(s)
Calcio , Hipoparatiroidismo , Humanos , Calcio/metabolismo , Fenotipo , Genotipo , ARN Mensajero , Hipoparatiroidismo/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo
3.
Am J Hum Genet ; 110(11): 1919-1937, 2023 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-37827158

RESUMEN

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease.


Asunto(s)
Anomalías Congénitas , Discapacidades del Desarrollo , N-Metiltransferasa de Histona-Lisina , Humanos , Mutación con Ganancia de Función , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Histonas/metabolismo , Lisina , Metilación , Metiltransferasas/genética , Neoplasias/genética , Drosophila/genética , Proteínas de Drosophila/genética , Discapacidades del Desarrollo/genética , Anomalías Congénitas/genética
4.
Eur J Hum Genet ; 2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-36973392

RESUMEN

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

5.
Am J Med Genet A ; 188(8): 2460-2465, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35642566

RESUMEN

The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations.


Asunto(s)
Síndrome CHARGE , Deformidades Congénitas de la Mano , Pérdida Auditiva Sensorineural , Micrognatismo , Anomalías Múltiples , Animales , Nervio Coclear , Cara/anomalías , Deformidades Congénitas de la Mano/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual , Ratones , Micrognatismo/genética , Cuello/anomalías , Factores de Transcripción SOXC
6.
Clin Genet ; 102(1): 72-77, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35347702

RESUMEN

Pathogenic variants in IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause a variety of neurodevelopmental disorders, with intellectual disability as a uniform feature. We report five cases, each with a novel missense variant in the pleckstrin homology (PH) domain of the IQSEC2 protein. Male patients all present with moderate to profound intellectual disability, significant delays or absent language and speech and variable seizures. We describe the phenotypic spectrum associated with missense variants in PH domain of IQSEC2, further delineating the genotype-phenotype correlation for this X-linked gene.


Asunto(s)
Encefalopatías , Discapacidad Intelectual , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Mutación , Fenotipo , Dominios Homólogos a Pleckstrina
7.
Pediatr Dermatol ; 39(2): 268-272, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35178752

RESUMEN

Generalized inflammatory peeling skin syndrome (PSS) is a rare autosomal recessive genodermatosis caused by loss-of-function disease-causing variants of the corneodesmosin gene (CDSN), resulting in excessive shedding of the superficial layers of the epidermis. We describe a case of generalized inflammatory PSS in an infant, presenting at day two of life with ichthyosiform erythroderma and superficial peeling of the skin. Hair microscopy showed trichorrhexis invaginata. Normal amounts of skin LEKT1, a product of SPINK5 on immunohistochemical staining excluded a diagnosis of Netherton syndrome. Genetic analysis revealed a homozygous novel complete CDSN deletion, estimated 4.6 kb in size, supporting the diagnosis of generalized inflammatory PSS.


Asunto(s)
Dermatitis Exfoliativa , Eosinofilia , Enfermedades del Cabello , Síndrome de Netherton , Enfermedades Cutáneas Genéticas , Dermatitis Exfoliativa/diagnóstico , Dermatitis Exfoliativa/genética , Dermatitis Exfoliativa/patología , Humanos , Lactante , Péptidos y Proteínas de Señalización Intercelular , Síndrome de Netherton/diagnóstico , Síndrome de Netherton/genética , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/genética
8.
J Pediatr Hematol Oncol ; 44(3): e743-e746, 2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-34310467

RESUMEN

We describe a female toddler with rectal bleeding from extensive colonic polyposis, and diagnosed with familial adenomatous polyposis. She has epilepsy from infancy attributed to focal cortical dysplasia. Hepatoblastoma was diagnosed at 13 months of age. Germline testing detected a pathogenic APC (adenomatous polyposis coli gene) variant. We discuss the anecdotal management of this case, including the clinical utility of genetic confirmation. We review the genotype-phenotype correlation of the APC mutational spectrum, and the existing evidence supporting the hypothesis that cortical dysplasia is part of the APC-related spectrum.


Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Hepáticas , Malformaciones del Desarrollo Cortical , Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Femenino , Genes APC , Estudios de Asociación Genética , Mutación de Línea Germinal , Humanos , Neoplasias Hepáticas/genética , Malformaciones del Desarrollo Cortical/genética
9.
Am J Med Genet A ; 188(4): 1299-1306, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34970864

RESUMEN

The beta-actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser-Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple-peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild-type S. cerevisiae strain. There was an obvious growth defect of the yACT1S348L/WT pseudoheterozygote compared to a yACT1WT/WT strain when grown at 22°C but not when grown at 30°C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild-type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.


Asunto(s)
Atresia Intestinal , Gemelos Monocigóticos , Actinas/genética , Actinas/metabolismo , Variación Biológica Poblacional , Anomalías Craneofaciales , Edema , Epilepsia , Facies , Humanos , Discapacidad Intelectual , Atresia Intestinal/diagnóstico , Atresia Intestinal/genética , Lisencefalia , Saccharomyces cerevisiae/metabolismo , Gemelos Monocigóticos/genética
10.
Eur J Hum Genet ; 29(9): 1405-1417, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33603160

RESUMEN

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.


Asunto(s)
Sordera/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Discapacidad Intelectual/genética , Mutación con Pérdida de Función , Proteínas de la Membrana/genética , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Sordera/patología , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Humanos , Discapacidad Intelectual/patología , Masculino , Mutación Missense , Linaje , Síndrome
11.
Mol Genet Genomic Med ; 8(11): e1508, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32969205

RESUMEN

BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases. METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18 months considered all disease-associated genes. At 25-34 months we reviewed all cases and the strategies which solved them. RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months. CONCLUSION: Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.


Asunto(s)
Secuenciación del Exoma/normas , Pruebas Genéticas/normas , Enfermedades Raras/genética , Análisis de Secuencia de ADN/normas , Pruebas Genéticas/métodos , Humanos , Enfermedades Raras/diagnóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos , Secuenciación del Exoma/métodos
13.
J Med Genet ; 57(7): 454-460, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31988067

RESUMEN

BACKGROUND: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.


Asunto(s)
Enanismo/genética , Glucuronosiltransferasa/genética , Cardiopatías Congénitas/genética , Hernia Umbilical/genética , Nucleotidasas/genética , Enanismo/patología , Femenino , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/patología , Hernia Umbilical/patología , Humanos , Masculino , Mutación Missense/genética , Fenotipo , Embarazo , Proteoglicanos , Secuenciación del Exoma
14.
J Hum Genet ; 64(12): 1173-1186, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31530938

RESUMEN

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.


Asunto(s)
Anomalías Múltiples/genética , Cara/anomalías , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Estudios de Cohortes , Estudios de Asociación Genética/métodos , Humanos
15.
Bone ; 121: 163-171, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30599297

RESUMEN

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with "corner fractures" (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of "corner fractures". An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extracellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and "corner fracture" appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.


Asunto(s)
Fibronectinas/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Densidad Ósea/genética , Enfermedades del Desarrollo Óseo/genética , Niño , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación/genética , Fenotipo , Reacción en Cadena de la Polimerasa , Adulto Joven
16.
Genet Med ; 21(4): 850-860, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30245513

RESUMEN

PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.


Asunto(s)
Discapacidades del Desarrollo/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Discapacidades del Desarrollo/fisiopatología , Exoma/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Mutación , Fenotipo , Isoformas de Proteínas/genética , Adulto Joven
17.
NPJ Genom Med ; 3: 18, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30062048

RESUMEN

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

18.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29861108

RESUMEN

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.


Asunto(s)
Estudios de Asociación Genética , Patrón de Herencia/genética , Mutación con Pérdida de Función/genética , Trastornos del Neurodesarrollo/genética , Proteínas Quinasas/genética , Adolescente , Adulto , Secuencia de Bases , Línea Celular , Niño , Preescolar , Facies , Femenino , Humanos , Lactante , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Translocación Genética , Adulto Joven
19.
Am J Hum Genet ; 101(5): 815-823, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29100092

RESUMEN

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.


Asunto(s)
Fibronectinas/genética , Fracturas Óseas/genética , Mutación/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/genética , Huesos/patología , Cartílago/patología , Niño , Preescolar , Exoma/genética , Femenino , Humanos , Masculino , Fenotipo , Escoliosis/genética
20.
JAMA Pediatr ; 171(9): 855-862, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28759686

RESUMEN

Importance: Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness. Objectives: To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory. Design, Setting, and Participants: This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing. Exposures: All children underwent singleton WES with targeted phenotype-driven analysis. Main Outcomes and Measures: The study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES. Results: Of 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway. Conclusions and Relevance: Singleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.


Asunto(s)
Enfermedades Genéticas Congénitas/diagnóstico , Análisis de Secuencia de ADN/métodos , Australia , Niño , Preescolar , Análisis Costo-Beneficio , Exoma/genética , Femenino , Enfermedades Genéticas Congénitas/economía , Humanos , Masculino , Mutación , Estudios Prospectivos , Análisis de Secuencia de ADN/economía
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