RESUMO
Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.
Assuntos
Proteínas de Ciclo Celular , Cistos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Criança , Humanos , Masculino , Proteínas de Ciclo Celular/genética , Cistos/genética , Cistos/diagnóstico por imagem , Variações do Número de Cópias de DNA/genética , Sequenciamento do Exoma , Duplicação Gênica , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Homozigoto , Imageamento por Ressonância Magnética , LinhagemRESUMO
The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate-limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper-IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other. In contrast, pathogenic variants reported in PMVK are heterozygous and associated with porokeratosis, a skin disorder with no systemic manifestations. Recently, biallelic variants in PMVK were reported as a cause for an autoinflammatory disorder for the first time in two unrelated patients. In this study, we describe a child with recurrent arthritis and a HIDS-like phenotype harboring a novel homozygous variant c.398 C>T (p.Ala133Val) in PMVK. Mononuclear cells isolated from the patient showed significantly elevated production of interleukin 1ß, a key cytokine that shapes the inflammatory response in HIDS. Protein modeling studies suggested potential defects in PMVK enzyme activity. These results posit a further expanding of the genotypic spectrum of autoinflammatory disease to include biallelic PMVK variants.
Assuntos
Deficiência de Mevalonato Quinase , Criança , Humanos , Genótipo , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/metabolismo , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genéticaRESUMO
The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.
Assuntos
Epilepsia , Aconselhamento Genético , Fenótipo , Humanos , Epilepsia/genética , Epilepsia/epidemiologia , Epilepsia/diagnóstico , Índia/epidemiologia , Masculino , Feminino , Criança , Pré-Escolar , Lactente , Predisposição Genética para Doença , Linhagem , Idade de Início , Estudos de Associação Genética , Adolescente , Genótipo , Variações do Número de Cópias de DNA/genéticaRESUMO
Nucleoporins (NUPs) are a group of transporter proteins that maintain homeostasis of nucleocytoplasmic transport of proteins and ribonucleic acids under physiological conditions. Biallelic pathogenic variants in NUP214 are known to cause susceptibility to acute infection-induced encephalopathy-9 (IIAE9, MIM#618426), which is characterized by severe and early-onset febrile encephalopathy causing neuroregression, developmental delay, microcephaly, epilepsy, ataxia, brain atrophy, and early death. NUP214-related IIAE9 has been reported in eight individuals from four distinct families till date. We identified a novel in-frame deletion, c.202_204del p.(Leu68del), in NUP214 by exome sequencing in a 20-year-old male with episodic ataxia, seizures, and encephalopathy, precipitated by febrile illness. Neuroimaging revealed progressive cerebellar atrophy. In silico predictions show a change in the protein conformation that may alter the downstream protein interactions with the NUP214 N-terminal region, probably impacting the mRNA export. We report this novel deletion in NUP214 as a cause for a late onset and less severe form of IIAE9.
Assuntos
Encefalopatia Aguda Febril , Encefalopatias , Epilepsia , Microcefalia , Masculino , Humanos , Adulto Jovem , Adulto , Encefalopatias/diagnóstico , Encefalopatias/genética , Epilepsia/genética , Microcefalia/genética , Atrofia , Complexo de Proteínas Formadoras de Poros Nucleares/genéticaRESUMO
Heterozygous disease-causing variants in BCL11B are the basis of a rare neurodevelopmental syndrome with craniofacial and immunological involvement. Isolated craniosynostosis, without systemic or immunological findings, has been reported in one of the 17 individuals reported with this disorder till date. We report three additional individuals harboring de novo heterozygous frameshift variants, all lying in the exon 4 of BCL11B. All three individuals presented with the common findings of this disorder i.e. developmental delay, recurrent infections with immunologic abnormalities and facial dysmorphism. Notably, craniosynostosis of variable degree was seen in all three individuals. We, thus add to the evolving genotypes and phenotypes of BCL11B-related BAFopathy and also review the clinical, genomic spectrum along with the underlying disease mechanisms of this disorder.
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Craniossinostoses , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Fatores de Transcrição/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Mutação da Fase de Leitura , Fenótipo , Proteínas Supressoras de Tumor/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Repressoras/genéticaRESUMO
The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.
Assuntos
Colina Quinase , Epilepsia , Microcefalia , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Alelos , Colina Quinase/genética , Epilepsia/genética , Humanos , Microcefalia/complicações , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Transtornos do Neurodesenvolvimento/genéticaRESUMO
Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Masculino , Animais , Camundongos , Cinesinas/genética , Neurônios/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Axônios , Córtex Cerebral/patologia , Deficiência Intelectual/patologiaRESUMO
Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.
Assuntos
Doenças do Sistema Nervoso Central/genética , Genômica , Leucoencefalopatias/genética , Malformações do Sistema Nervoso/genética , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Programas de Rastreamento , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Sequenciamento do ExomaRESUMO
OBJECTIVE: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. METHODS: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. RESULTS: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. CONCLUSION: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.
Assuntos
Autopsia , Anormalidades Congênitas/genética , Sequenciamento do Exoma , Feto , Fenótipo , Diagnóstico Pré-Natal , Estudos de Associação Genética , Humanos , Estudos RetrospectivosRESUMO
Metachromatic leukodystrophy due to Arylsulfatase A enzyme deficiency is an autosomal recessive disorder caused by biallelic variations in ARSA gene. Till date 186 variations have been reported in ARSA gene worldwide, but the variation spectrum in India is not known. The aim of this study was to identify the variation profile in Indian patients presenting with features of Arylsulfatase A deficient metachromatic leukodystrophy. We sequenced the ARSA gene in 51 unrelated families and identified 36 variants out of which 16 were novel. The variations included 23 missense, 3 nonsense, and 6 frameshift variants (3 single-base deletions and 3 single-base duplications), 1 indel, one 3 bp deletion, and 2 splice site variations. The pathogenicity of the novel variations was inferred with the help of mutation prediction softwares like MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using in silico methods. The most common variation was c.931 C > T(p.Arg311*), found in 11.4% (14 out of 122 alleles) of the tested individuals. To the best of our knowledge, this study is the first of its kind in India with respect to the size of the cohort and the molecular diagnostic method used and one of the largest cohorts of metachromatic leukodystrophy studied till date.
Assuntos
Cerebrosídeo Sulfatase/genética , Leucodistrofia Metacromática/genética , Splicing de RNA/genética , Adolescente , Adulto , Alelos , Povo Asiático , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Índia/epidemiologia , Lactente , Leucodistrofia Metacromática/patologia , Masculino , Mutação , Adulto JovemRESUMO
Malan syndrome and Marshall-Smith syndrome (MSS) are allelic disorders caused by mutation in NFIX gene. We report a 3-year- 6 months- old female with clinical features suggestive of Malan syndrome with mutation in exon 2 of NFIX gene. NFIX gene, where most of the mutations in Malan syndrome are located. She did not have advanced bone age. The radiographs of long bones showed metaphyseal changes which were not reported previously. This study reports the first mutation proven case from India and highlights the overlap between MSS and Malan syndrome.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Estudos de Associação Genética , Genótipo , Fatores de Transcrição NFI/genética , Fenótipo , Displasia Septo-Óptica/diagnóstico , Displasia Septo-Óptica/genética , Alelos , Pré-Escolar , Análise Mutacional de DNA , Éxons , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Mutação , RadiografiaRESUMO
LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only 31 individuals from 18 families have been reported with this rare condition. Exome sequencing was done in two affected individuals from two unrelated families. Additionally, phenotypic, and genotypic information from the literature was reviewed. Two novel homozygous missense variants, c.2207G>A p. (Arg736His) and c.1157C>G p. (Ser386Ter) in LPIN2 , were identified in family 1 and family 2 respectively. Chronic recurrent osteomyelitis involving the lower extremities was the most common clinical presentation. LPIN2 -related Majeed syndrome should be considered as a differential diagnosis in an individual with clinical or radiological evidence of recurrent sterile osteomyelitis and chronic anaemia.
Assuntos
Anemia Diseritropoética Congênita , Síndromes de Imunodeficiência , Osteomielite , Humanos , Osteomielite/diagnóstico , Osteomielite/genética , Anemia Diseritropoética Congênita/diagnóstico , Síndrome , Proteínas NuclearesRESUMO
Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding the CPLANE complex result in a wide variety of skeletal dysplasia with disturbed ciliary functions. The phenotypic spectrum includes orofaciodigital syndrome and short rib polydactyly syndrome. FUZ, as a part of the CPLANE complex, is involved in intraflagellar vesicular trafficking within primary cilia. Previously, the variants, c.98_111+9del and c.851G>T in FUZ were identified in two individuals with a skeletal ciliopathy, manifesting digital anomalies (polydactyly, syndactyly), orofacial cleft, short ribs and cardiac defects. Here, we present two novel variants, c.601G>A and c.625_636del in biallelic state, in two additional subjects exhibiting phenotypic overlap with the previously reported cases. Our findings underscore the association between biallelic loss of function variants in FUZ and skeletal ciliopathy akin to orofaciodigital syndrome.
Assuntos
Síndromes Orofaciodigitais , Humanos , Síndromes Orofaciodigitais/genética , Síndromes Orofaciodigitais/patologia , Masculino , Feminino , Mutação com Perda de Função , Fenótipo , AlelosRESUMO
Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4. Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2-23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910_1911del and c.2816_2817del) were identified in homozygous state in PRG4. We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India.
RESUMO
INTRODUCTION: KCNK18 , a potassium channel subfamily K member 18 (MIM*613655), encodes for TWIK-related spinal cord K+ channel (TRESK) and is important for maintaining neuronal excitability. Monoallelic variants in KCNK18 are known to cause autosomal dominant migraine, with or without aura, susceptibility to, 13 (MIM#613656). Recently, biallelic missense variants in KCNK18 have been reported in three individuals from a non-consanguineous family with intellectual disability, developmental delay, autism spectrum disorder (ASD), and seizure. METHODS: Singleton exome sequencing was performed for the proband after detailed clinical evaluation to identify the disease-causing variants in concordance with the phenotype. RESULTS: We herein report an individual with intellectual disability, developmental delay, ASD, and epilepsy with febrile seizure plus with a novel homozygous stopgain variant, c.499C>T p.(Arg167Ter) in KCNK18 . CONCLUSION: This report further validates KCNK18 as a cause of autosomal recessive intellectual disability, epilepsy, and ASD.
Assuntos
Transtorno do Espectro Autista , Epilepsia , Deficiência Intelectual , Convulsões Febris , Humanos , Deficiência Intelectual/genética , Convulsões Febris/genética , Epilepsia/genética , Mutação de Sentido Incorreto , Canais de Potássio/genéticaRESUMO
The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.
RESUMO
Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM# 611726) is a rare autosomal recessive condition associated with pathogenic variants in KCTD7, which encodes the BR-C,ttk and bab/pox virus and zinc finger domain-containing KCTD7 protein. We report four individuals from three Indian families presenting with an initial period of normal development, progressive myoclonic seizures followed by neuroregression and an abnormal electroencephalogram. We identified two novel missense variants, c.458G>C p.(Arg153Pro) and c.205C>G p.(Leu69Val) and one known disease-causing variant, c.280C>T p.(Arg94Trp) in KCTD7 by exome sequencing. We review the literature of 67 individuals with variants in KCTD7. Our study expands the molecular spectrum of KCTD7-related progressive myoclonic epilepsy.
Assuntos
Epilepsias Mioclônicas Progressivas , Canais de Potássio , Humanos , Mutação de Sentido Incorreto , Epilepsias Mioclônicas Progressivas/genética , Canais de Potássio/genética , Sequenciamento do ExomaRESUMO
Developmental and epileptic encephalopathies (DEE) are a genetically heterogeneous group of disorders characterised by early onset epilepsy, epileptiform activity on electroencephalogram and associated developmental delay or neuroregression. With the advent of high throughput sequencing, novel gene-disease associations have been described for DEEs. Voltage activated sodium channels (Nav) regulate neuronal excitability. Fibroblast growth factor homologous factors (FHFs) are proteins, which bind to the C terminal cytoplasmic tails of alpha subunits of Nav channels and influence their function and surface expression. Gain of function hemizygous or heterozygous variants in FGF13 (also known as FHF2) were recently identified as the cause for X-linked developmental and epileptic encephalopathy 90 (DEE90; MIM# 301058) in seven individuals from five families, which included one female. We report an additional female, providing further evidence for a novel de novo heterozygous missense variant in FGF13, NM_004114.5: c.14T > G p.(Ile5Ser) causing X-linked DEE90. In addition, we review the genotype and phenotype of affected individuals with DEE90.
Assuntos
Epilepsia/genética , Fatores de Crescimento de Fibroblastos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Feminino , Genótipo , Heterozigoto , Humanos , Lactente , Mutação de Sentido Incorreto , FenótipoRESUMO
Disorders of intracellular cobalamin metabolism are a group of metabolic disorders that lead to varied clinical presentation from intrauterine life to adulthood. We report a male infant with developmental regression, macrocytic anaemia and hyperpigmentation. Exome sequencing identified a homozygous pathogenic variant in the MMADHC gene, known to cause homocystinuria, cblD type (MIM #277410). We describe significant clinical improvement with targeted therapy and emphasise the relevance of genomic testing in accurate management of inherited metabolic disorders.
Assuntos
Homocistinúria , Deficiência de Vitamina B 12 , Adulto , Homocistinúria/complicações , Homocistinúria/diagnóstico , Homocistinúria/genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Fatores de Transcrição , Vitamina B 12/uso terapêuticoRESUMO
Exome sequencing is gaining popularity as a genomic test for the diagnosis of Mendelian disorders in children. It is essential for pediatricians to familiarize themselves with this technique and its interpretation. This brief review discusses some of the key components of a clinical or research report on exome sequencing for a practicing pediatrician, so as to enable them to utilize this test well and provide timely referrals to a clinical geneticist.