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BACKGROUND: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented. METHODS: Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals. RESULTS: We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. CONCLUSIONS: An Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Judeus/genética , Homozigoto , SíndromeRESUMO
BACKGROUND: SINO syndrome (Spastic paraplegia, Intellectual disability, Nystagmus and Obesity) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising eight with SINO and four with an autosomal recessive condition attributed to bi-allelic KIDINS220 variants. METHODS: In our international cohort, we have comprised 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed clinical and molecular data of our cohort and previously reported individuals and based on functional experiments reached a better understanding of the pathogenesis behind KIDINS220-related disease. RESULTS: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. 92% had their diagnosis within three years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted. CONCLUSION: Our study provides further insights into the clinical spectrum, etiology and predicted functional impact of KIDINS220 variants.
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Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.
Assuntos
Disceratose Congênita/genética , Retardo do Crescimento Fetal/genética , Mutação em Linhagem Germinativa/genética , Deficiência Intelectual/genética , Microcefalia/genética , Serina Proteases/genética , Adulto , Criança , Pré-Escolar , Disceratose Congênita/patologia , Feminino , Retardo do Crescimento Fetal/patologia , Células HeLa , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Linhagem , Estrutura Terciária de Proteína , Deleção de Sequência/genética , Serina Proteases/química , Complexo Shelterina , Telomerase/metabolismo , Proteínas de Ligação a Telômeros/metabolismoRESUMO
Danforth's short tail (Sd) mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10 000 live births. Sd animals exhibit aberrant axial skeleton, urogenital and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, vertebral-anal-cardiac-tracheo-esophageal fistula-renal-limb (VACTERL) association and persistent cloaca. Previous studies have shown that the Sd mutation results from an endogenous retroviral (ERV) insertion upstream of the Ptf1a gene resulting in its ectopic expression at E9.5. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue, which revealed minimal changes in chromatin accessibility in Sd/Sd mutant embryos. Interestingly, chromatin changes were localized to a small interval adjacent to the Sd ERV insertion overlapping a known Ptf1a enhancer region, which is conserved in mice and humans. Furthermore, mRNA-seq experiments revealed increased transcription of Ptf1a target genes and, importantly, downregulation of hedgehog pathway genes. Reduced sonic hedgehog (SHH) signaling was confirmed by in situ hybridization and immunofluorescence suggesting that the Sd phenotype results, in part, from downregulated SHH signaling. Taken together, these data demonstrate substantial transcriptome changes in the Sd mouse, and indicate that the effect of the ERV insertion on Ptf1a expression may be mediated by increased chromatin accessibility at a conserved Ptf1a enhancer. We propose that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways.
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Montagem e Desmontagem da Cromatina , Cromatina/genética , Cromatina/metabolismo , Epigenoma , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Transcriptoma , Animais , Biomarcadores , Biologia Computacional/métodos , Elementos Facilitadores Genéticos , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Camundongos , Mutação , Organogênese/genética , Fenótipo , Regiões Promotoras GenéticasRESUMO
PURPOSE: The SARS-CoV-2 pandemic abruptly altered medical education and clinical care. This work evaluates trainee perspectives of the impact of the pandemic on medical genetics education. METHODS: A Qualtrics survey was sent to physician trainees who rotated in genetics before or midpandemic. Questions assessed patient care, didactic education, and competency in multiple domains. Number of clinic visits completed by trainees were collated through review of documentation. RESULTS: Twenty-three rotating residents completed the surveys. Five of the pediatric residents completed the elective during the pandemic. All residents participated in virtual care during the pandemic, and rotating residents reported an improvement in self-assessed competency in multiple domains. Potential weak areas of education midpandemic included dysmorphology and genetic counseling. CONCLUSION: Residents on a genetics elective can gain crucial skills and knowledge even when the rotation is in a primarily virtual format. Supplemental dysmorphology and genetic counseling education may improve remote educational experiences. Further research across institutions may deepen understanding of the impact of the pandemic on education in genetics.
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COVID-19 , Educação Médica , Genética Médica , Internato e Residência , Criança , Humanos , Pandemias , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.
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Anormalidades Congênitas/genética , Análise Mutacional de DNA , Sequenciamento do Exoma , Testes Genéticos , Mutação , Anormalidades Congênitas/diagnóstico , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Based on audio recordings of consultations in three U.S. paediatric multidisciplinary Disorders of Sex Development-Intersex clinics, we examine the process of gender assignment of children with "atypical" genitalia. Rather than fully determined by the presence of biological sex traits, the gender assignment discussion hinges on how clinician and parent collaboratively imagine different aspects of what constitutes being a gendered person. They orient towards the potential for sexual intimacy, fertility, gender dysphoria, stigma, and gonadal cancer risk. While these futures remain inherently uncertain, clinicians and parents plan to mobilise gender socialisation and medical interventions to render their choice of gender a self-fulfilling prophecy. Gender destinies capture that the child always had a specific, innate gender awaiting discovery, and presumes a project for medical and social monitoring, intervention, correction, and optimisation.
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Tomada de Decisões , Transtornos do Desenvolvimento Sexual/cirurgia , Identidade de Gênero , Pais/psicologia , Incerteza , Adulto , Pré-Escolar , Transtornos do Desenvolvimento Sexual/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estigma SocialRESUMO
De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Histonas/metabolismo , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação , Fatores de Transcrição/metabolismo , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Insuficiência de Crescimento/metabolismo , Insuficiência de Crescimento/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Genes Dominantes , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/metabolismo , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Cultura Primária de Células , Ligação Proteica , Síndrome , Fatores de Transcrição/genética , Transcriptoma , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , UbiquitinaçãoRESUMO
We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.
Assuntos
Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Doenças Neurodegenerativas/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Elementos E-Box , Fácies , Família , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Lactente , Padrões de Herança , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Mutação , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Linhagem , Fenótipo , Transdução de Sinais , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Adulto Jovem , Peixe-ZebraRESUMO
Following the principles of care recommended in the 2006 Consensus Statement on Disorders of Sex Development (DSD), along with input from representatives of peer support and advocacy groups, this study surveyed DSD clinical management practices at healthcare facilities in the United States. DSD are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. Facilities providing care for patients with DSD were targeted for participation. Specialty providers completed a survey with questions in six broad categories: Institution Information, Nomenclature and Care Guidelines, Interdisciplinary Services, Staff and Community Education, DSD Management, and Research. Twenty-two of 36 targeted sites (61%) participated. Differences were observed between sites with regard to what conditions were considered to be DSD. All sites reported some degree of involvement of pediatric urology and/or surgery and pediatric endocrinology in the care of DSD patients. Gynecology and neonatology were most frequently not represented. Wide variation was observed across sites in continuing education standards, obtaining informed consent for clinical procedures, and in specific clinical management practices. This survey is the first to assess DSD clinical management practices in the United States. The findings establish a baseline of current practices against which providers delivering care to these patients and their families can benchmark their efforts. Such surveys also provide a practical framework for collaboration in identifying opportunities for change that enhance health and quality of life outcomes for patients and families affected by DSD.
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Transtornos do Desenvolvimento Sexual/epidemiologia , Transtornos do Desenvolvimento Sexual/genética , Inquéritos e Questionários , Atenção à Saúde , Transtornos do Desenvolvimento Sexual/fisiopatologia , Feminino , Humanos , Masculino , Qualidade de Vida , Processos de Determinação Sexual , Estados Unidos/epidemiologiaRESUMO
Investigation of disorders of sex development (DSD) has resulted in the discovery of multiple sex-determining genes. MAP3K1 encodes a signal transduction regulator in the sex determination pathway and is emerging as one of the more common genes responsible for 46,XY DSD presenting as complete or partial gonadal dysgenesis. Clinical assessment, endocrine evaluation, and genetic analysis were performed in six individuals from four unrelated families with 46,XY DSD. All six individuals were found to have likely pathogenic MAP3K1 variants. Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral streak gonads with typical internal and external female genitalia, while the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development, resulting in clitoral hypertrophy with otherwise typical female external genitalia. Testing for MAP3K1 variants should be considered in patients with 46,XY complete or partial gonadal dysgenesis, particularly in families with multiple members affected with 46,XY DSD. Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/genética , Disgenesia Gonadal/genética , MAP Quinase Quinase Quinase 1/genética , Diferenciação Sexual/genética , Adolescente , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Feminino , Disgenesia Gonadal/fisiopatologia , Humanos , Masculino , Mutação , LinhagemRESUMO
Sex assignment at birth remains one of the most clinically challenging and controversial topics in 46,XY disorders of sexual development (DSD). This is particularly challenging in deficiency of 5-alpha reductase type 2 given that external genitalia are typically undervirilized at birth but typically virilize at puberty to a variable degree. Historically, most individuals with 5-alpha reductase deficiency were raised females. However, reports that over half of patients who underwent a virilizing puberty adopted an adult male gender identity have challenged this practice. Consensus guidelines on assignment of sex of rearing at birth are equivocal or favor male assignment in the most virilized cases. While a male sex of rearing assignment may avoid lifelong hormonal therapy and/or allow the potential for fertility, female sex assignment may be more consistent with external anatomy in the most severely undervirilized cases. Herein, we describe five patients with 46,XY DSD due 5-alpha-reductase type 2 deficiency, all with a severe phenotype. An inter-disciplinary DSD medical team at one of two academic centers evaluated each patient. This case series illustrates the complicated decision-making process of assignment of sex of rearing at birth in 5-alpha reductase type 2 deficiency and the challenges that arise when the interests of the child, parental wishes, recommendations of the medical team, and state law collide.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Processos de Determinação Sexual , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adulto , Criança , Pré-Escolar , Di-Hidrotestosterona/metabolismo , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Desenvolvimento Embrionário/genética , Feminino , Humanos , Hipospadia/fisiopatologia , Lactente , Cariótipo , Masculino , Maturidade Sexual/genética , Erros Inatos do Metabolismo de Esteroides/fisiopatologiaRESUMO
Carriers of isodicentric Y (idicY) mosaicism exhibit a wide range of clinical features, including short stature, gonadal abnormalities, and external genital anomalies. However, the phenotypic spectrum for individuals carrying an idicY and a 46, XX cell line is less clearly defined. A more complete description of the phenotype related to idicY is thus essential to guide management related to pubertal development, fertility, and gonadoblastoma risk in mosaic carriers. Findings from the evaluation of twin females with an abnormal karyotype, 48, XX, +idic(Yq) x2/47, XX, +idic(Yq)/46, XX, are presented to highlight the importance of interdisciplinary care in the management of multifaceted disorders of sex development.
Assuntos
Cariótipo Anormal , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Transtornos do Desenvolvimento Sexual/genética , Mosaicismo , Aberrações dos Cromossomos Sexuais , Adolescente , Transtornos Cognitivos/genética , Feminino , Humanos , Gêmeos/genéticaRESUMO
The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. These findings in human BEEC cohorts are underscored by the recent description of BEEC(-like) murine knock-out models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal uro-rectal development leading to the BEEC, demonstrating the importance of ISL1-pathway in human and mouse and propose SLC20A1 and CELSR3 as the first BEEC candidate genes, identified through systematic whole-exome sequencing (WES) in BEEC patients.
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The semidominant Danforth's short tail (Sd) mutation arose spontaneously in the 1920s. The homozygous Sd phenotype includes severe malformations of the axial skeleton with an absent tail, kidney agenesis, anal atresia, and persistent cloaca. The Sd mutant phenotype mirrors features seen in human caudal malformation syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. The Sd mutation was previously mapped to a 0.9 cM region on mouse chromosome 2qA3. We performed Sanger sequencing of exons and intron/exon boundaries mapping to the Sd critical region and did not identify any mutations. We then performed DNA enrichment/capture followed by next-generation sequencing (NGS) of the critical genomic region. Standard bioinformatic analysis of paired-end sequence data did not reveal any causative mutations. Interrogation of reads that had been discarded because only a single end mapped correctly to the Sd locus identified an early transposon (ETn) retroviral insertion at the Sd locus, located 12.5 kb upstream of the Ptf1a gene. We show that Ptf1a expression is significantly upregulated in Sd mutant embryos at E9.5. The identification of the Sd mutation will lead to improved understanding of the developmental pathways that are misregulated in human caudal malformation syndromes.
Assuntos
Elementos de DNA Transponíveis/genética , Mutagênese Insercional/genética , Análise de Sequência de DNA , Fatores de Transcrição , Animais , Desenvolvimento Embrionário , Éxons , Regulação da Expressão Gênica no Desenvolvimento/genética , Genoma , Humanos , Camundongos , Fenótipo , Medula Espinal/anormalidades , Cauda/anatomia & histologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
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Deficiência Intelectual , Proteínas de Membrana , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Feminino , Masculino , Transtornos do Neurodesenvolvimento/genética , Alelos , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Criança , Pré-Escolar , Diferenciação Celular/genética , Proteínas Supressoras de TumorRESUMO
Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular dysgenesis. The region responsible for the gonadal dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY gonadal dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY gonadal dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete gonadal dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.
Assuntos
Disgenesia Gonadal 46 XY/genética , Gonadoblastoma/genética , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Feminino , Disgenesia Gonadal 46 XY/patologia , Gonadoblastoma/patologia , Humanos , Lactente , Recém-Nascido , Cariotipagem , Literatura de Revisão como AssuntoRESUMO
Polyalanine repeat expansion diseases are hypothesized to result from unequal chromosomal recombination, yet mechanistic studies are lacking. We identified two de novo cases of hand-foot-genital syndrome (HFGS) associated with polyalanine expansions in HOXA13 that afforded rare opportunities to investigate the mechanism. The first patient with HFGS was heterozygous for a de novo nine codon polyalanine expansion. Haplotype investigation showed that the expansion arose on the maternally inherited chromosome but not through unequal crossing over between homologs, leaving unequal sister chromatid exchange during mitosis or meiosis or slipped mispairing as possible explanations. The asymptomatic father of the second patient with HFGS was mosaic for a six codon polyalanine expansion. Multiple tissue PCR and clonal analysis of paternal fibroblasts showed only expansion/WT and WT/WT clones, and haplotype data showed that two unaffected offspring inherited the same paternal allele without the expansion, supporting a postzygotic origin. Absence of the contracted allele in the mosaic father does not support sister chromatid exchange in the origin of the expansion. Mosaicism for HOXA13 polyalanine expansions may be associated with a normal phenotype, making examination of parental DNA essential in apparently de novo HFGS cases to predict accurate recurrence risks. We could not find an example in the literature where unequal sister chromatid exchange has been proven for any polyalanine expansion, suggesting that the principal mechanism for polyalanine expansions (and contractions) is slipped mispairing without repair or that the true frequency of unequal sister chromatid exchange involving these repeats is low.
Assuntos
Anormalidades Múltiplas/genética , Expansão das Repetições de DNA/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Proteínas de Homeodomínio/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , Peptídeos , FenótipoRESUMO
The shelterin complex at mammalian telomeres contains the single-stranded DNA-binding protein Pot1, which regulates telomere length and protects chromosome ends. Pot1 binds Tpp1, the shelterin component that connects Pot1 to the duplex telomeric DNA-binding proteins Trf1 and Trf2. Control of telomere length requires that Pot1 binds Tpp1 as well as the single-stranded telomeric DNA, but it is not known whether the protective function of Pot1 depends on Tpp1. Alternatively, Pot1 might function similarly to the Pot1-like proteins of budding and fission yeast, which have no known Tpp1-like connection to the duplex telomeric DNA. Using mutant mouse cells with diminished Tpp1 levels, RNA interference directed to mouse Tpp1 and Pot1, and complementation of mouse Pot1 knockout cells with human and mouse Pot1 variants, we show here that Tpp1 is required for the protective function of mammalian Pot1 proteins.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas de Ligação a Telômeros/metabolismo , Proteínas de Ligação a Telômeros/fisiologia , Telômero/metabolismo , Animais , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Camundongos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/fisiologia , Interferência de RNA , Complexo Shelterina , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/antagonistas & inibidores , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/fisiologia , Proteínas de Ligação a Telômeros/genética , Proteína 2 de Ligação a Repetições TeloméricasRESUMO
People with cloacal malformation and 46,XX cloacal exstrophy are at risk of developing Müllerian outflow tract obstruction (OTO). Management of OTO requires expertise of many medical and surgical specialties. The primary presenting symptom associated with OTO is cyclical and later continuous pain and can be initially quelled with hormonal suppression as a temporizing measure to allow for patient maturation. The decision for timing and method of definitive treatment to establish a patent outflow tract that can also be used for penetrative sexual activity and potential fertility is a complicated one and incredibly variable based on patient age alone. To understand the management approach to OTO, we put forth five phases with associated recommendations: (1) caregiver and patient education and evaluation before obstruction; (2) presentation, diagnosis, and symptom temporization; (3) readiness assessment; (4) peri-procedural management; (5) long-term surveillance. This review will emphasize the importance of interdisciplinary team management of the complex shared medical, surgical, and psychological decision making required to successfully guide developing patients with outflow obstruction secondary to cloacal malformations and cloacal exstrophy through adolescence.