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BACKGROUND: Current developments in genetic strategies result in tracing an underlying genetic defect in the majority of neurodevelopmental disorders (NDD) patients, including those with normal functioning as well as intellectual disabilities. These genetic NDD are increasingly detected and still often underexposed in psychiatric practice. AIM: To improve (early) detection of these genetic NDD to contribute to psychiatric diagnostics and treatment, with the emphasis on reducing the mental vulnerabilities per developmental stage. METHOD: Overview of developments based on literature and guidelines. RESULTS: Early detection includes both biological and environmental factors and provides tools for specific diagnostic procedures and treatment strategies. Within scientific research there is a tendency to translational research, which includes all levels from cell to the entire organism. This offers new insights and possibilities for personalized treatment. CONCLUSION: The current fragmented knowledge on these rare disorders needs to be bundled in the upcoming years. There is a lot of ground to be gained for psychiatric practice in this area.
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Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/terapiaRESUMO
This Article was originally published under a CC BY-NC-SA 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
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Canais de Cloreto/genética , Síndromes Epilépticas/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Canais de Cloreto/metabolismo , Epilepsia/genética , Síndromes Epilépticas/fisiopatologia , Família , Feminino , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Humanos , Deficiência Intelectual/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Oócitos , Linhagem , Fenótipo , Síndrome , Substância Branca/fisiopatologia , Xenopus laevisRESUMO
BACKGROUND: Kabuki syndrome (KS) is a Mendelian disorder, characterised by short stature, facial dysmorphisms and developmental delay and/or intellectual disability. Clarification of the neurocognitive profile in KS may provide directions for education and treatment interventions for KS. Previous studies on cognitive functioning in KS are scarce and have mainly focused on the general level of intelligence. The few more extensive studies suggested weaknesses in language skills, visuoconstruction, perceptual reasoning and speed of information processing. Other relevant domains such as memory, executive functioning and social cognition have not been studied yet. METHOD: This is the first study in which cognitive functioning within multiple domains is systematically explored in 29 participants with KS (age range: 5-48 years) and compared to both norm groups (healthy population) and an appropriate control group of 15 individuals with other genetic syndromes (age range: 6-28 years). RESULTS: Compared to the norm groups of the cognitive test manuals, as expected, participants with KS show a weaker performance on all cognitive tests. Comparison with the more appropriate genetic control group indicates weaknesses in visuoconstruction and visual memory and no weaknesses in planning, cognitive flexibility or social cognition. Verbal memory seems to be a relative strength. CONCLUSIONS: Individuals with KS suffer from specific weaknesses in visuoconstruction, in addition to their intellectual disability/developmental delay. These impairments in visuoconstruction plausibly result from problems in visual perceptual processing, which highlight the importance of the use of auditory cues instead of visual cues in targeted educational support and psychosocial interventions.
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Anormalidades Múltiplas/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Função Executiva/fisiologia , Face/anormalidades , Doenças Genéticas Inatas/fisiopatologia , Doenças Hematológicas/fisiopatologia , Deficiência Intelectual/fisiopatologia , Desempenho Psicomotor/fisiologia , Percepção Social , Doenças Vestibulares/fisiopatologia , Percepção Visual/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Disfunção Cognitiva/etiologia , Deficiências do Desenvolvimento/etiologia , Face/fisiopatologia , Feminino , Doenças Genéticas Inatas/complicações , Doenças Hematológicas/complicações , Humanos , Deficiência Intelectual/etiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doenças Vestibulares/complicações , Adulto JovemRESUMO
Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Krüppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency.
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Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Fatores de Transcrição Kruppel-Like/genética , Adolescente , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/psicologia , Feminino , Predisposição Genética para Doença , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/psicologia , Masculino , Mutação de Sentido Incorreto/genética , Sequenciamento do ExomaRESUMO
Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Caseína Quinase II/química , Caseína Quinase II/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Face/fisiopatologia , Feminino , Genótipo , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Conformação Proteica , Dobramento de Proteína , Sequenciamento do Exoma/métodosRESUMO
De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome.
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Proteína Quinase CDC2/genética , Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Códon sem Sentido , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias Congênitas/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Sítios de Splice de RNA/genética , Adulto JovemRESUMO
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.
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Deficiência Intelectual/genética , Alelos , Consanguinidade , Exoma/genética , Família , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Humanos , Mutação , Paquistão , Linhagem , Sequenciamento do Exoma/métodosRESUMO
The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.
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Transtorno Autístico/genética , Proteínas de Transporte/genética , Variação Genética , Deficiência Intelectual/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Transtorno Autístico/diagnóstico , Sequência de Bases , Criança , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Deficiência Intelectual/diagnóstico , Cariotipagem , Masculino , Mutação de Sentido Incorreto , Fenótipo , Proteólise , Splicing de RNA , Análise de Sequência de DNARESUMO
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
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Transtorno Autístico/genética , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Convulsões Febris/genética , Irmãos , Distúrbios da Fala/genética , Transtorno de Movimento Estereotipado/genética , Síndrome , Adulto Jovem , Quinases DyrkRESUMO
Many of the patients who attend the outpatient mental health clinics already have a long history of psychiatric problems. Their symptoms seem easy to classify, but the misdiagnosis of the patients' underlying problems can lead to a long series of costly referrals as inpatients or to an ineffective treatment outcome. In this article we focus on three patients whose history and background circumstances had been analysed in detail and who had also been subjected to a genetic analysis. The analyses pointed to an etiology-based diagnosis which had important implications for their future treatment and its outcome.
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Erros de Diagnóstico/psicologia , Transtornos Mentais/diagnóstico , Adulto , Custos Hospitalares , Humanos , Masculino , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFß3, TGFßR1, TGFßR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
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Anodontia/genética , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Associação Genética , Anodontia/fisiopatologia , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Regulação da Expressão Gênica/genética , Ontologia Genética , Genótipo , Humanos , Especificidade de Órgãos , Fenótipo , Biossíntese de Proteínas/genéticaRESUMO
As whole exome sequencing (WES) is just starting to be used as a diagnostic tool in paediatric neurology for children with a neurological disorder, and patient experiences and preferences with regard to counselling are relatively underexplored. This article explores experiences and preferences of parents with pre-test and post-test counselling in a trial that uses WES for diagnostics. Second, it maps information and communication needs which exceed the counselling protocol, in order to acquire insight into how it can be improved. Data were gathered through in-depth interviews with parents of 15 children who were included in the trial. Information and communication needs of parents differed from the protocol with respect to (i) the type and amount of information provided about WES research, (ii) incidental findings, (iii) communication about progress of the study, and (iv) the communication of the results. Furthermore, parents preferred to have more of a communicative exchange with health care providers about their daily struggles and concerns related to their life with a diseased child and wanted to know how a diagnosis could offer help. There are different ways to meet parental needs, but we suggest that assigning a case manager might be a helpful option that deserves further exploration.
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Comunicação , Aconselhamento , Exoma/genética , Neurologia/métodos , Pais , Pediatria , Análise de Sequência de DNA/métodos , Criança , Humanos , Achados Incidentais , Consentimento Livre e Esclarecido , Encaminhamento e ConsultaRESUMO
Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.
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Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Sequência de Aminoácidos , Sítios de Ligação/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Fenótipo , Síndrome de Rett/genética , Síndrome de Rett/patologia , Homologia de Sequência de AminoácidosRESUMO
De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.
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Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Epilepsia/genética , Deficiência Intelectual/genética , Adolescente , Síndrome de Cornélia de Lange/fisiopatologia , Resistência a Medicamentos/genética , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Éxons/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/genética , Deleção de SequênciaRESUMO
The use of whole exome sequencing (WES) for diagnostics of children with rare genetic diseases raises questions about best practices in genetic counselling. While a lot of attention is now given to pre-test counselling procedures for WES, little is known about how parents experience the (positive, negative, or inconclusive) WES results in daily life. To fill this knowledge gap, data were gathered through in-depth interviews with parents of 15 children who underwent WES analysis. WES test results, like results from other genetic tests, evoked relief as well as worries, irrespective of the type of result. Advantages of obtaining a conclusive diagnosis included becoming more accepting towards the situation, being enabled to attune care to the needs of the child, and better coping with feelings of guilt. Disadvantages experienced included a loss of hope for recovery, and a loss by parents of their social network of peers and the effort necessary to re-establish that social network. While parents with conclusive diagnoses were able to re-establish a peer community with the help of social media, parents receiving a possible diagnosis experienced hurdles in seeking peer support, as peers still needed to be identified. These types of psychosocial effects of WES test results for parents are important to take into account for the development of successful genetic counselling strategies.
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Adaptação Psicológica , Aconselhamento Genético/psicologia , Testes Genéticos , Pais/psicologia , Doenças Raras/genética , Adulto , Criança , Exoma , Humanos , Doenças Raras/diagnóstico , Análise de Sequência de DNARESUMO
KCNH1 mutations have recently been described in six individuals with Temple-Baraitser syndrome (TMBTS) and six individuals with Zimmermann-Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for "lumping" or for "splitting" of TMBTS and ZLS.
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Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Fibromatose Gengival/patologia , Hallux/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Unhas Malformadas/patologia , Polegar/patologiaRESUMO
Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.
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Anormalidades Múltiplas/genética , Blefaroptose/congênito , Duplicação Cromossômica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Adulto , Animais , Blefaroptose/genética , Estatura/genética , Criança , Fissura Palatina/genética , Feminino , Dedos/anormalidades , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino , Camundongos , Camundongos Transgênicos , Microcefalia/genética , SíndromeRESUMO
Until recently, the cause of intellectual disability (ID) remained unexplained in at least 50% of affected individuals. Recent advances in genetic technologies led to great new opportunities to elucidate genetic defects implicated in ID. The introduction of genome-wide technologies that are able to detect small chromosomal copy number variations led to the identification of several microdeletion/duplication syndromes and to the subsequent identification of single causative genes. By the recent implementation of whole exome sequencing (WES) in research and diagnostics, with the potential to identify disease causing variants throughout the human exome at the base-pair level, a new revolution has started. Several studies showed that WES is effective in the identification of ID genes. Here we provide an historical overview of the advances in diagnostics of ID and illustrate the high diagnostic potential of current technologies by presenting the diagnostic survey that we performed in a series of 253 individuals with previously unexplained ID. This is the first study that systematically evaluated the diagnostic yield of the currently available and rapidly developing genetic diagnostic arsenal. The results of our study indicate that application of present-day genetic diagnostic technologies lead to a significant increase in the number of patients that can be diagnosed.
Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Exoma/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/genética , Fenótipo , Sequência de Bases , Estudos de Coortes , Proteína do X Frágil da Deficiência Intelectual/genética , Testes Genéticos/tendências , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Padrões de Herança/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Dados de Sequência Molecular , Países BaixosRESUMO
BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.