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Pathogenic and likely pathogenic variants in the TECRL gene are known to be associated with recessive catecholaminergic polymorphic ventricular tachycardia 3, which can include prolonged QT intervals (MIM#614021). We report a case of cardiac arrest in a previously healthy adolescent male in the community. The patient was found to have a novel maternally inherited likely pathogenic variant in TECRL (c.915T>G [p.Tyr305Ter]) and an additional 19-kb duplication encompassing multiple exons of TECRL (chr4:65165944-65185287, dup [4q13.1]) not identified in the mother. Genetic results were revealed via rapid whole-genome sequencing, which allowed appropriate treatment and prognostication.
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Taquicardia Ventricular , Humanos , Taquicardia Ventricular/genética , Masculino , Adolescente , Linhagem , Mutação , Eletrocardiografia , Predisposição Genética para Doença , Sequenciamento Completo do GenomaRESUMO
Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
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Deleção Cromossômica , Cromossomos Humanos Par 22 , Meningomielocele , Animais , Feminino , Humanos , Masculino , Camundongos , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Sequenciamento do Exoma , Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Meningomielocele/epidemiologia , Meningomielocele/genética , Penetrância , Disrafismo Espinal/genética , Risco , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
A central question for regenerative neuroscience is whether synthetic neural circuits, such as those built from two species, can function in an intact brain. Here, we apply blastocyst complementation to selectively build and test interspecies neural circuits. Despite approximately 10-20 million years of evolution, and prominent species differences in brain size, rat pluripotent stem cells injected into mouse blastocysts develop and persist throughout the mouse brain. Unexpectedly, the mouse niche reprograms the birth dates of rat neurons in the cortex and hippocampus, supporting rat-mouse synaptic activity. When mouse olfactory neurons are genetically silenced or killed, rat neurons restore information flow to odor processing circuits. Moreover, they rescue the primal behavior of food seeking, although less well than mouse neurons. By revealing that a mouse can sense the world using neurons from another species, we establish neural blastocyst complementation as a powerful tool to identify conserved mechanisms of brain development, plasticity, and repair.
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Neurônios , Animais , Camundongos , Ratos , Neurônios/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Blastocisto/metabolismo , Blastocisto/citologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Encéfalo/citologia , Encéfalo/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Especificidade da Espécie , Camundongos Endogâmicos C57BL , MasculinoRESUMO
PURPOSE: Copy-number variants (CNVs) and other non-single nucleotide variant/indel variant types contribute an important proportion of diagnoses in individuals with suspected genetic disease. This study describes the range of such variants detected by genome sequencing (GS). METHODS: For a pediatric cohort of 1032 participants undergoing clinical GS, we characterize the CNVs and other non-single nucleotide variant/indel variant types that were reported, including aneuploidies, mobile element insertions, and uniparental disomies, and we describe the bioinformatic pipeline used to detect these variants. RESULTS: Together, these genetic alterations accounted for 15.8% of reported variants. Notably, 67.9% of these were deletions, 32.9% of which overlapped a single gene, and many deletions were reported together with a second variant in the same gene in cases of recessive disease. A retrospective medical record review in a subset of this cohort revealed that up to 6 additional genetic tests were ordered in 68% (26/38) of cases, some of which failed to report the CNVs/rare variants reported on GS. CONCLUSION: GS detected a broad range of reported variant types, including CNVs ranging in size from 1 Kb to 46 Mb.
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Genoma , Genômica , Humanos , Criança , Estudos Retrospectivos , Mapeamento Cromossômico , Nucleotídeos , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.
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Epilepsia , Malformações do Desenvolvimento Cortical , Humanos , Multiômica , Encéfalo/metabolismo , Epilepsia/genética , Mutação , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/metabolismoRESUMO
BACKGROUND: Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation. METHODS: We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole-genome or whole-exome sequencing (WGS, WES). We replicated our analyses in a separate cohort of 60 cases collected from five academic medical centers. For comparison, we also analyzed these cases with current state-of-the-art variant prioritization tools. Included in the comparisons were trio, duo, and singleton cases. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted from clinical notes by two means: manually and using an automated clinical natural language processing (CNLP) tool. Finally, 14 previously unsolved cases were reanalyzed. RESULTS: GEM ranked over 90% of the causal genes among the top or second candidate and prioritized for review a median of 3 candidate genes per case, using either manually curated or CNLP-derived phenotype descriptions. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top candidate and in 19/20 within the top five, irrespective of whether SV calls were provided or inferred ab initio by GEM using its own internal SV detection algorithm. GEM showed similar performance in absence of parental genotypes. Analysis of 14 previously unsolved cases resulted in a novel finding for one case, candidates ultimately not advanced upon manual review for 3 cases, and no new findings for 10 cases. CONCLUSIONS: GEM enabled diagnostic interpretation inclusive of all variant types through automated nomination of a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing cost and expediting case review.
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Inteligência Artificial , Doenças Raras/genética , Bases de Dados Genéticas , Feminino , Genômica/métodos , Genótipo , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Sequenciamento do ExomaRESUMO
Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
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Crescimento e Desenvolvimento , Mosaicismo , Espermatozoides/metabolismo , Adolescente , Envelhecimento/sangue , Alelos , Células Clonais , Estudos de Coortes , Humanos , Masculino , Modelos Biológicos , Mutação/genética , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
Visceral myopathies (VMs) encompass a spectrum of disorders characterized by chronic disruption of gastrointestinal function, with or without urinary system involvement. Pathogenic missense variation in smooth muscle γ-actin gene (ACTG2) is associated with autosomal dominant VM. Whole-genome sequencing of an infant presenting with chronic intestinal pseudo-obstruction revealed a homozygous 187 bp (c.589_613 + 163del188) deletion spanning the exon 6-intron 6 boundary within ACTG2 The patient's clinical course was marked by prolonged hospitalizations, multiple surgeries, and intermittent total parenteral nutrition dependence. This case supports the emerging understanding of allelic heterogeneity in ACTG2-related VM, in which both biallelic and monoallelic variants in ACTG2 are associated with gastrointestinal dysfunction of similar severity and overlapped clinical presentation. Moreover, it illustrates the clinical utility of rapid whole-genome sequencing, which can comprehensively and precisely detect different types of genomic variants including small deletions, leading to guidance of clinical care decisions.
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Actinas/genética , Genótipo , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/genética , Humanos , Íleus , Lactente , Pseudo-Obstrução Intestinal/patologia , Masculino , Linhagem , Resultado do Tratamento , Sequenciamento Completo do GenomaRESUMO
Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.
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Epilepsia/genética , Proteínas Ativadoras de GTPase/genética , Hemimegalencefalia/genética , Convulsões/genética , Serina-Treonina Quinases TOR/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Hemimegalencefalia/tratamento farmacológico , Hemimegalencefalia/patologia , Humanos , Recém-Nascido , Convulsões/patologia , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Rapid whole-genome sequencing (rWGS) allows for a diagnosis to be made quickly and impact medical management, particularly in critically ill children. Variants identified by this approach are often not identified using other testing methodologies, such as carrier screening or gene sequencing panels, targeted panels, or chromosomal microarrays. However, rWGS can identify variants of uncertain significance (VUSs), which challenges clinicians in the rapid return of information to families. Here we present a case of the metabolic condition D-bifunctional protein deficiency in a neonate with epilepsy and hypotonia born to consanguineous parents. Sequencing revealed a homozygous VUS in HSD17B4, c.1619A > G (p.His540Arg). Preliminary results were delivered within 3 d of sample receipt. Previous parental carrier screening included the HSD17B4 gene but was reported as negative. The molecular finding directed the clinical team to assess phenotypic overlap and investigate next steps in terms of confirmation of the findings and potential medical management of the patient. Clinical metabolic testing of fatty acids confirmed the diagnosis. Computational analysis of HSD17B4 His540Arg showed the change to likely impact dimerization based on structural insights, with the histidine conserved and selected throughout all 223 species assessed for this amino acid. This variant clusters around several pathogenic and likely pathogenic variants in HSD17B4 This case demonstrates the utility of rWGS, the potential for receiving uncertain results, and the downstream implications for confirmation or rejection of a molecular diagnosis by the clinical team.
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Homozigoto , Proteína Multifuncional do Peroxissomo-2/deficiência , Proteína Multifuncional do Peroxissomo-2/genética , Deficiência de Proteína/genética , Sequenciamento Completo do Genoma , Ácidos Graxos , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Modelos Moleculares , Hipotonia Muscular , Patologia Molecular/métodos , Proteína Multifuncional do Peroxissomo-2/química , Conformação ProteicaRESUMO
To investigate the diagnostic and clinical utility of a partially automated reanalysis pipeline, forty-eight cases of seriously ill children with suspected genetic disease who did not receive a diagnosis upon initial manual analysis of whole-genome sequencing (WGS) were reanalyzed at least 1 year later. Clinical natural language processing (CNLP) of medical records provided automated, updated patient phenotypes, and an automated analysis system delivered limited lists of possible diagnostic variants for each case. CNLP identified a median of 79 new clinical features per patient at least 1 year later. Compared to a standard manual reanalysis pipeline, the partially automated pipeline reduced the number of variants to be analyzed by 90% (range: 74%-96%). In 2 cases, diagnoses were made upon reinterpretation, representing an incremental diagnostic yield of 4.2% (2/48, 95% CI: 0.5-14.3%). Four additional cases were flagged with a possible diagnosis to be considered during subsequent reanalysis. Separately, copy number analysis led to diagnoses in two cases. Ongoing discovery of new disease genes and refined variant classification necessitate periodic reanalysis of negative WGS cases. The clinical features of patients sequenced as infants evolve rapidly with age. Partially automated reanalysis, including automated re-phenotyping through CNLP, has the potential to identify molecular diagnoses with reduced expert labor intensity.
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BACKGROUND: In diagnosis of rare genetic diseases we face a decision as to the degree to which the sequencing lab offers one or more diagnoses based on clinical input provided by the clinician, or the clinician reaches a diagnosis based on the complete set of variants provided by the lab. We tested a software approach to assist the clinician in making the diagnosis based on clinical findings and an annotated genomic variant table, using cases already solved using less automated processes. RESULTS: For the 81 cases studied (involving 216 individuals), 70 had genetic abnormalities with phenotypes previously described in the literature, and 11 were not described in the literature at the time of analysis ("discovery genes"). These included cases beyond a trio, including ones with different variants in the same gene. In 100% of cases the abnormality was recognized. Of the 70, the abnormality was ranked #1 in 94% of cases, with an average rank 1.1 for all cases. Large CNVs could be analyzed in an integrated analysis, performed in 24 of the cases. The process is rapid enough to allow for periodic reanalysis of unsolved cases. CONCLUSIONS: A clinician-friendly environment for clinical correlation can be provided to clinicians who are best positioned to have the clinical information needed for this interpretation.
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Doenças Raras , Software , Variações do Número de Cópias de DNA , Genômica , Humanos , Fenótipo , Doenças Raras/diagnóstico , Doenças Raras/genéticaRESUMO
Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
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Aciltransferases/genética , Moléculas de Adesão Celular/genética , Doenças Cerebelares/genética , Epilepsia/genética , Variação Genética/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Alelos , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Malformações do Sistema Nervoso/genética , Linhagem , SíndromeRESUMO
OBJECTIVES: Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME. METHODS: Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5. RESULTS: These results strengthen the hypothesis that somatic variants in PI3K-Akt-mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation. SIGNIFICANCE: In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.
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PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
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Encefalopatias , Microcefalia , Animais , Proliferação de Células/genética , Homozigoto , Humanos , Camundongos , Microcefalia/genética , Peixe-Zebra/genéticaRESUMO
Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.
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Atenção à Saúde , Mortalidade Infantil , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/mortalidade , Medicina de Precisão , Alelos , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo dos Metais/etiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. METHODS: We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole-exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. RESULTS: PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN-variant. The PDLIM5 loss-of-function (LoF) variant affected all cardiac-specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN-variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb-deletion of exon 2 in PDLIM5 resulting in early-onset cardiac disease, showing the importance of PDLIM5 in cardiac function. CONCLUSIONS: Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early-onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Cardiomiopatia Dilatada/genética , Genes Modificadores , Proteínas com Domínio LIM/genética , Mutação com Perda de Função , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Cardiomiopatia Dilatada/diagnóstico , Proteínas de Transporte/genética , Conectina/genética , Feminino , Testes Genéticos , Humanos , Proteínas com Domínio LIM/metabolismo , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Miocárdio/metabolismo , Linhagem , Sequenciamento do ExomaRESUMO
De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.