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1.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
2.
Nat Commun ; 12(1): 2558, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963192

RESUMO

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/genética , Alelos , Sequência de Aminoácidos , Animais , Pré-Escolar , Deficiências do Desenvolvimento/genética , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Feminino , Técnicas de Silenciamento de Genes , Ontologia Genética , Células HEK293 , Humanos , Mutação com Perda de Função , Masculino , Hipotonia Muscular/genética , Dissinergia Cerebelar Mioclônica/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Polimorfismo de Nucleotídeo Único , RNA-Seq , Ribonucleoproteínas Nucleares Pequenas/genética , Rigor Mortis/genética , Proteínas do Complexo SMN/metabolismo
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 419-424, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974247

RESUMO

Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical validation of CMA, the development and updating of technical standards and guidelines and their diagnostic impacts. The main focuses were on the development and updating of expert consensus, practice resources, and a series of technical standards and guidelines through systematic review of case series with CMA application in the literature. Expert consensus and practice resource supported the use of CMA as the first-tier testing for detecting chromosomal abnormalities and CNV in developmental and intellectual disabilities, multiple congenital anomalies and autism. The standards and guidelines have been applied to pre- and postnatal testing for constitutional CNV and tumor testing for acquired CNV. CMA has significantly improved the diagnostic yields but still needs to overcome its technical limitations and face challenges of new technologies. Guiding and governing CMA through expert consensus, practice resource, standards and guidelines in the United States has provided effective and safe diagnostic services to patients and their families, reliable diagnosis on related genetic diseases for clinical database and basic research, and references for clinical translation of new technologies.


Assuntos
Variações do Número de Cópias de DNA , Deficiência Intelectual , Criança , Aberrações Cromossômicas , Cromossomos , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genética , Análise em Microsséries , Estados Unidos
4.
Methods Mol Biol ; 2262: 3-18, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977468

RESUMO

Analysis of cancer and RASopathy genetic databases reveals that ~19% of all cancer cases and ~4% of developmental disorders contain Ras mutations. Ras isoform and mutation variants differentially contribute to these diseases and provide an opportunity for deeper understanding of Ras function. The putative mechanisms underpinning these differences, new approaches that are being applied, and some of the key questions and challenges that remain are discussed.


Assuntos
Deficiências do Desenvolvimento/patologia , Mutação , Neoplasias/patologia , Proteínas ras/genética , Deficiências do Desenvolvimento/genética , Humanos , Neoplasias/genética
5.
Eur J Endocrinol ; 185(1): 57-66, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33909591

RESUMO

Patients with deletions on chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole-genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with the patient's Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole-exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2) but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.


Assuntos
Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Perda Auditiva Neurossensorial/genética , Defeitos dos Septos Cardíacos/genética , Síndrome de Kallmann/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/complicações , Enzimas Reparadoras do DNA/genética , Deficiências do Desenvolvimento/complicações , Deleção de Genes , Haploinsuficiência , Perda Auditiva Neurossensorial/complicações , Defeitos dos Septos Cardíacos/complicações , Humanos , Canais Iônicos/genética , Síndrome de Kallmann/complicações , Fatores de Transcrição Kruppel-Like/genética , Masculino , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Análise de Sequência de RNA , Síndrome , Sequenciamento Completo do Exoma
7.
Eur J Med Genet ; 64(4): 104181, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33647455

RESUMO

In a consanguineous Pakistani kinship afflicted with mild to moderate intellectual disability (ID), mild lissencephaly, brain atrophy and skeletal anomalies, we detected homozygous CRADD c.2T > G (p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8), two good candidates 1.85-Mb apart that segregated with the disorder. Biallelic damaging variants in CRADD cause recessive mental retardation-34 (MRT34; MIM 614499) with mild to moderate ID, "thin" lissencephaly, and variable megalencephaly and seizures. For USP44, only a single ID family has been reported with a homozygous deleterious variant, which is the same as the variant we detected. In affected individuals we present, at ages 29-32 years, clinical findings are similar yet not fully concordant with phenotypes for either gene considering the skeletal findings, and ID is not as severe as would be expected for defects in two genes with additive effect. Some variable CRADD-related features such as language impairment and seizures are not observed in the presented family. The presence of the two variants in the family is a very rare example of familial linked homozygous variants, and whether the damaging USP44 variant contributed to the disease in the family we present is not clear. As for the skeletal findings, facial dysmorphism and digestive problems, we did not find a candidate variant. This study is an example of both clinical variation and difficulty in variant detection and evaluation. Our findings highlight that even an extensive exome sequence analysis can fail to fully uncover the complex molecular basis of a syndrome even if potentially causative variants are identified.


Assuntos
Proteína Adaptadora de Sinalização CRADD/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Lisencefalia/genética , Anormalidades Musculoesqueléticas/genética , Estrabismo/genética , Ubiquitina Tiolesterase/genética , Adulto , Consanguinidade , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Lisencefalia/patologia , Masculino , Anormalidades Musculoesqueléticas/patologia , Mutação , Linhagem , Estrabismo/patologia , Síndrome
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 228-231, 2021 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-33751530

RESUMO

OBJECTIVE: To assess the value of copy number variations (CNVs) and chromosomal karyotyping analysis for patients with intellectual disability/developmental delay (ID/DD). METHODS: Chromosomal karyotype analysis was applied to 530 children diagnosed with ID/DD. Single nucleotide polymorphism array (SNP-array) was further applied for 120 children with unknown etiology. RESULTS: Among the 530 children with ID/DD, 104 (19.62%) were detected with chromosomal abnormalities. For the 120 children analyzed by SNP-array, 44 (36.67%) were detected with CNVs, among which 20 were predicted as pathogenic, 6 as likely pathogenic, 10 as variants of unknown significance, 7 as likely benign,and 1 as loss of heterozygosity. CONCLUSION: SNP-array can facilitate delineation of the etiology of patients with ID/DD, which may provide a basis for their prognosis, consultation and clinical intervention.


Assuntos
Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , Aberrações Cromossômicas , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Cariotipagem
9.
Genet Med ; 23(6): 1158-1162, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33531666

RESUMO

PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. METHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. RESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. CONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , Deficiências do Desenvolvimento/genética , Mutação da Fase de Leitura , Homozigoto , Humanos , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Linhagem , Fenótipo , Convulsões/genética
10.
Genet Med ; 23(6): 1058-1064, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33603196

RESUMO

PURPOSE: The clinical and psychosocial outcomes associated with receiving a genetic diagnosis for developmental disorders are wide-ranging but under-studied. We sought to investigate outcomes from a subset of families who received a diagnosis through the Deciphering Developmental Disorders (DDD) study. METHODS: Individuals recruited through the Peninsula Clinical Genetics Service who received a confirmed genetic diagnosis through the DDD study before August 2019 (n = 112) were included in a clinical audit. Families with no identified clinical outcomes (n = 16) were invited to participate in semistructured telephone interviews. RESULTS: Disease-specific treatment was identified for 7 probands (6%), while 48 probands (43%) were referred for further investigations or screening and 60 probands (54%) were recruited to further research. Just 5 families (4%) opted for prenatal testing in a subsequent pregnancy, reflecting the relatively advanced maternal age in our cohort, and 42 families (38%) were given disease-specific information or signposting to patient-specific resources such as support groups. Six interviews were performed (response rate = 47%) and thematic analysis identified four major themes: reaching a diagnosis, emotional impact, family implications, and practical issues. CONCLUSION: Our data demonstrate that receiving a genetic diagnosis has substantial positive medical and psychosocial outcomes for the majority of patients and their families.


Assuntos
Deficiências do Desenvolvimento , Testes Genéticos , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Emoções , Feminino , Humanos , Gravidez , Encaminhamento e Consulta
11.
Eur J Med Genet ; 64(4): 104166, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33571694

RESUMO

CHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies.


Assuntos
Anormalidades Craniofaciais/genética , DNA Helicases/genética , Deficiências do Desenvolvimento/genética , Megalencefalia/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Comportamento Social , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Humanos , Masculino , Megalencefalia/patologia , Mutação , Síndrome , Adulto Jovem
12.
Genet Med ; 23(5): 872-880, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33564151

RESUMO

PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos Psicóticos , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Criança , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética
13.
Eur J Paediatr Neurol ; 31: 61-69, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33640666

RESUMO

OBJECTIVE: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay. METHODS: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature. RESULTS: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy. CONCLUSIONS: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Guanilato Quinases/genética , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos
14.
J Paediatr Child Health ; 57(4): 477-483, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33566436

RESUMO

Genomic testing for a genetic diagnosis is becoming standard of care for many children, especially those with a syndromal intellectual disability. While previously this type of specialised testing was performed mainly by clinical genetics teams, it is increasingly being 'mainstreamed' into standard paediatric care. With the introduction of a new Medicare rebate for genomic testing in May 2020, this type of testing is now available for paediatricians to order, in consultation with clinical genetics. Children must be aged less than 10 years with facial dysmorphism and multiple congenital abnormalities or have global developmental delay or moderate to severe intellectual disability. This rebate should increase the likelihood of a genetic diagnosis, with accompanying benefits for patient management, reproductive planning and diagnostic certainty. Similar to the introduction of chromosomal microarray into mainstream paediatrics, this genomic testing will increase the number of genetic diagnoses, however, will also yield more variants of uncertain significance, incidental findings, and negative results. This paper aims to guide paediatricians through the process of genomic testing, and represents the combined expertise of educators, clinical geneticists, paediatricians and genomic pathologists around Australia. Its purpose is to help paediatricians navigate choosing the right genomic test, consenting patients and understanding the possible outcomes of testing.


Assuntos
Deficiência Intelectual , Pediatria , Idoso , Austrália , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Testes Genéticos , Genômica , Humanos , Deficiência Intelectual/genética , Medicare , Estados Unidos
15.
Nat Commun ; 12(1): 833, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547280

RESUMO

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.


Assuntos
Deficiências do Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento , Microcefalia/genética , Micrognatismo/genética , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Adolescente , Sequência de Aminoácidos , Animais , Criança , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero , Feminino , Humanos , Lisina/análogos & derivados , Lisina/genética , Lisina/metabolismo , Masculino , Microcefalia/metabolismo , Microcefalia/patologia , Micrognatismo/metabolismo , Micrognatismo/patologia , Fatores de Iniciação de Peptídeos/deficiência , Peptídeos/genética , Peptídeos/metabolismo , Biossíntese de Proteínas , Conformação Proteica , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Espermidina/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Genet Med ; 23(5): 881-887, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33473207

RESUMO

PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Sequenciamento Completo do Exoma
17.
Nat Commun ; 12(1): 627, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504798

RESUMO

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.


Assuntos
Deficiências do Desenvolvimento/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Cromossomos Humanos X/genética , Feminino , Genes Recessivos , Humanos , Padrões de Herança/genética , Masculino , Herança Multifatorial/genética , Mutação/genética , Fenótipo , Caracteres Sexuais
18.
Genet Med ; 23(4): 669-678, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33402738

RESUMO

PURPOSE: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. METHODS: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. RESULTS: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. CONCLUSION: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , China/epidemiologia , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética
19.
Eur J Med Genet ; 64(2): 104133, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33387673

RESUMO

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM_001197104.2:c.4433delG; p. Arg1478LeufsTer108). This boy presented a WDSTS phenotype associated with broad neurodevelopmental features, including an unusual speech difficulty (i.e., palilalia), and brain imaging studies revealed an array of cortical anomalies (e.g., frontal simplified gyration, focal frontal cortical dysplasia). These clinical and radiological observations expand the known WDSTS-related neurodevelopmental phenotypes and further strengthen the important role of KMT2A in brain function and cortical development.


Assuntos
Deficiências do Desenvolvimento/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Malformações do Desenvolvimento Cortical/genética , Proteína de Leucina Linfoide-Mieloide/genética , Córtex Cerebral/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/patologia , Síndrome
20.
J Med Case Rep ; 15(1): 28, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494837

RESUMO

BACKGROUND: Developmental disabilities (DD) are an umbrella term for conditions associated with functional impairments in physical, learning, language, or behavior areas. Intellectual disability (ID) is a type of developmental disability that results in delays in cognitive or intellectual functioning, such as reasoning, learning, and problem-solving, and adaptive behaviors including social and practical life skills. DD can be due to a variety of factors, ranging from environmental exposures to genetic mutations, and studies suggest that up to 40% of DDs may be caused by genetic issues. CASE PRESENTATION: In this case study, we present an 18-year-old internationally adopted female Chinese American patient with a known history of developmental delay, intellectual disability, strabismus, and a congenital heart defect who had not been tested for genetic causes of her delay prior to presentation. When evaluated with chromosomal microarray, the patient demonstrated a deletion on the short arm of chromosome 5, an area associated with Cri-du-chat syndrome. This chromosomal deletion was a likely explanation for her history of developmental delays, intellectual disability, and congenital heart defect, in addition to her history of institutionalization and the trauma of multiple caregiver transitions in early childhood. The patient was referred for further evaluation by a geneticist and genetic counselor. CONCLUSIONS: This case highlights that the underlying cause of developmental delay is often multifactorial, and underscores the importance of a full medical evaluation, including genetic testing, for children with intellectual disability. Using this approach, healthcare professionals can identify potential diagnoses and provide more targeted resources to families.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Análise em Microsséries
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