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1.
Am J Med Genet A ; 179(5): 832-836, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30803155

RESUMO

Interstitial deletions within the chromosomal region 2q24.2 have already been linked to intellectual disability (ID) in the past. In most cases the described patients showed a syndromic form of ID associated with large deletions containing multiple genes. Here we describe a family with two siblings with mild non-syndromic ID. They shared the same 564 kb deletion in the chromosomal region 2q24.2 containing only the TANK gene, which was inherited from the similarly affected father, thus suggesting haploinsufficiency of TANK as a novel cause of non-syndromic ID. TANK encodes the TRAF family member-associated NF-kappa-B activator (OMIM #603893), which is expressed in many tissues. It functions as an adapter protein that interacts with the NF-kappa-B pathway and SOX11, an essential transcription factor in regeneration, survival and differentiation of the neuronal system. TANK has not been linked to ID or other human diseases before. To further elucidate the role of TANK in non-syndromic ID, we screened a cohort of 288 TANK deletion negative non-syndromic mental retardation patients for TANK mutations without identifying any pathogenic variant.

2.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

3.
Hum Mol Genet ; 27(8): 1343-1352, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29432577

RESUMO

CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c.2002A>G (p.I668V). By analyzing protein expression and processing, we did not observe any differences of the p.I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p.R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p.I668V variant, but not the pathogenic p.R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p.I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.

4.
Mol Genet Genomic Med ; 5(6): 774-780, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29178640

RESUMO

BACKGROUND: Johanson-Blizzard syndrome (JBS, MIM #243800) is a very rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, nasal wing hypoplasia, hypodontia, and other abnormalities. JBS is caused by mutations of the UBR1 gene (MIM *605981), encoding a ubiquitin ligase of the N-end rule pathway. METHODS: Molecular findings in a total of 65 unrelated patients with a clinical diagnosis of JBS who were previously screened for UBR1 mutations by Sanger sequencing were reviewed and cases lacking a disease-causing UBR1 mutation on either one or both alleles were included in this study. In order to discover mutations that are not detectable by Sanger sequencing, we designed a probe set for multiplex ligation-dependent probe amplification (MLPA) analysis of the UBR1 gene and analyzed the copy number status of all 47 UBR1 exons. RESULTS: Our previous studies using Sanger sequencing could detect mutations in 93.1% of 130 disease-associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this study. MLPA analysis detected six alleles harboring exon deletions/duplications, thereby raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles). CONCLUSION: We conclude that single or multi-exon deletions or duplications account for a substantial proportion of JBS-associated UBR1 mutations.


Assuntos
Anus Imperfurado/genética , Displasia Ectodérmica/genética , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Hipotireoidismo/genética , Deficiência Intelectual/genética , Nariz/anormalidades , Pancreatopatias/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Alelos , Anus Imperfurado/diagnóstico , Sequência de Bases , Criança , Pré-Escolar , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Análise Mutacional de DNA , Displasia Ectodérmica/diagnóstico , Éxons , Feminino , Deleção de Genes , Duplicação Gênica , Genótipo , Transtornos do Crescimento/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Hipotireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , Masculino , Reação em Cadeia da Polimerase Multiplex , Pancreatopatias/diagnóstico , Fenótipo
5.
Eur J Hum Genet ; 25(7): 823-831, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28594414

RESUMO

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , GTP Fosfo-Hidrolases/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Proteínas de Membrana/genética , Síndrome de Noonan/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Fenótipo
6.
Mol Syndromol ; 6(5): 210-21, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26997941

RESUMO

We present 2 cases with multiple de novo supernumerary marker chromosomes (sSMCs), each derived from a different chromosome. In a prenatal case, we found mosaicism for an sSMC(4), sSMC(6), sSMC(9), sSMC(14) and sSMC(22), while a postnatal case had an sSMC(4), sSMC(8) and an sSMC(11). SNP-marker segregation indicated that the sSMC(4) resulted from a maternal meiosis II error in the prenatal case. Segregation of short tandem repeat markers on the sSMC(8) was consistent with a maternal meiosis I error in the postnatal case. In the latter, a boy with developmental/psychomotor delay, autism, hyperactivity, speech delay, and hypotonia, the sSMC(8) was present at the highest frequency in blood. By comparison to other patients with a corresponding duplication, a minimal region of overlap for the phenotype was identified, with CHRNB3 and CHRNA6 as dosage-sensitive candidate genes. These genes encode subunits of nicotinic acetylcholine receptors (nAChRs). We propose that overproduction of these subunits leads to perturbed component stoichiometries with dominant negative effects on the function of nAChRs, as was shown by others in vitro. With the limitation that in each case only one sSMC could be studied, our findings demonstrate that different meiotic errors lead to multiple sSMCs. We relate our findings to age-related aneuploidy in female meiosis and propose that predivision sister-chromatid separation during meiosis I or II, or both, may generate multiple sSMCs.

7.
Neurology ; 86(10): 954-62, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865513

RESUMO

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Proteínas Munc18/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Adulto Jovem
8.
Eur J Hum Genet ; 24(4): 556-61, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26153216

RESUMO

Intellectual disability (ID) affects 2-3% of the population. In the past, many genetic causes of ID remained unidentified due to its vast heterogeneity. Recently, whole exome sequencing (WES) studies have shown that de novo variants underlie a significant portion of sporadic cases of ID. Applying WES to patients with ID or global developmental delay at different centers, we identified three individuals with distinct de novo variants in HIVEP2 (human immunodeficiency virus type I enhancer binding protein), which belongs to a family of zinc-finger-containing transcriptional proteins involved in growth and development. Two of the variants were nonsense changes, and one was a 1 bp deletion resulting in a premature stop codon that was reported previously without clinical detail. In silico prediction programs suggest loss-of-function in the mutated allele leading to haploinsufficiency as a putative mechanism in all three individuals. All three patients presented with moderate-to-severe ID, minimal structural brain anomalies, hypotonia, and mild dysmorphic features. Growth parameters were in the normal range except for borderline microcephaly at birth in one patient. Two of the patients exhibited behavioral anomalies including hyperactivity and aggression. Published functional data suggest a neurodevelopmental role for HIVEP2, and several of the genes regulated by HIVEP2 are implicated in brain development, for example, SSTR-2, c-Myc, and genes of the NF-κB pathway. In addition, HIVEP2-knockout mice exhibit several working memory deficits, increased anxiety, and hyperactivity. On the basis of the genotype-phenotype correlation and existing functional data, we propose HIVEP2 as a causative ID gene.


Assuntos
Códon sem Sentido , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Pré-Escolar , Exoma , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Adulto Jovem
9.
Am J Med Genet A ; 167A(11): 2685-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25974318

RESUMO

The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis of which is dysregulated signal flow through the RAS-MAPK pathway. Mutations in several components or modifiers of the pathway have been identified in Noonan syndrome and related disorders. Over the past years copy number variants (CNVs) encompassing RAS pathway genes (PTPN11, RAF1, MEK2, or SHOC2) have been reported in children with developmental syndromes. These observations raised speculations that the associated phenotypes represent RASopathies, implying that the increased or reduced expression of the respective RAS pathway component and a consecutive dysregulation of RAS pathway signalling is responsible for the clinical picture. Herein, we present two individuals and three of their relatives harboring duplications of either 3p25.2 including the RAF1 locus or 19p13.3 including the MEK2 locus. Duplication carriers exhibited variable clinical phenotypes including non-specific facial dysmorphism, short stature, and learning difficulties. A careful review of the literature supported the impression that phenotypes associated with CNVs including RAS pathway genes commonly share non-specific symptoms with RASopathies, while the characteristic "gestalt" is lacking. Considering the known molecular pathogenesis of RASopathies, it is questionable that a modest increase in the expression of a functionally normal signaling component can mimic the effects of a qualitatively abnormal (hyperactive) mutant protein. We thus argue that current empirical and biological evidence is still insufficient to allow the conclusion that an altered copy number of a RAS pathway component is indeed the mechanism that is critical for the phenotype associated with CNVs including RASopathy genes.


Assuntos
Variações do Número de Cópias de DNA/genética , Genes ras , Transdução de Sinais/genética , Proteínas ras/genética , Adolescente , Adulto , Pré-Escolar , Facies , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
11.
Am J Med Genet A ; 164A(12): 3162-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25251209

RESUMO

HIBCH (3-hydroxyisobutyryl-CoA hydrolase) deficiency (MIM #250620) is a rare autosomal recessive inborn error of metabolism, leading to a block in the catabolic pathway of the amino acid valine and presumably to accumulation of toxic valine metabolites in mitochondria. Only three families with HIBCH deficiency and biallelic HIBCH mutations have been described. We report on a further patient, first child of healthy consanguineous parents, with severe developmental delay, seizures, hyperintensities of the basal ganglia on magnetic resonance imaging (MRI), progressive brain atrophy, optic nerve atrophy, repeatedly elevated blood lactate, and respiratory chain complexes I, I + III and cytochrome c oxidase deficiencies with borderline depletion of mitochondrial DNA in muscle tissue. Laboratory findings in blood and skeletal muscle were inconsistent and did not allow a definite diagnosis, but supported the hypothesis of mitochondrial dysfunction. Homozygosity mapping and whole-exome sequencing revealed a homozygous one-base pair insertion in HIBCH. Deficiency of enzyme activity was confirmed in cultured fibroblasts. Although relatively unspecific, the clinical features were similar to those of the previously reported cases. Given the clinical variability and large number of differential diagnoses, the prevalence of HIBCH deficiency is probably underestimated. Next-generation sequencing approaches are an effective tool for identifying the underlying genetic basis in patients suspected of mitochondrial disorders.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Doenças Mitocondriais/patologia , Fenótipo , Tioléster Hidrolases/deficiência , Sequência de Bases , Western Blotting , Encéfalo/patologia , Exoma/genética , Fibroblastos/metabolismo , Humanos , Imagem por Ressonância Magnética , Doenças Mitocondriais/genética , Dados de Sequência Molecular , Músculo Esquelético/patologia , Linhagem , Análise de Sequência de DNA/métodos , Tioléster Hidrolases/genética
12.
Hum Mutat ; 35(12): 1495-505, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25224183

RESUMO

Glycoprotein M6A (GPM6A) is a neuronal transmembrane protein of the PLP/DM20 (proteolipid protein) family that associates with cholesterol-rich lipid rafts and promotes filopodia formation. We identified a de novo duplication of the GPM6A gene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increased GPM6A levels. An increase of patient-derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences of GPM6A dosage alterations in an intact nervous system, we employed Drosophila melanogaster as a model organism. We found that knockdown of Drosophila M6, the sole member of the PLP family in flies, in the wing, and whole organism causes malformation and lethality, respectively. These phenotypes as well as the protrusions of patient-derived lymphoblastoid cells with increased GPM6A levels can be alleviated by cholesterol supplementation. Notably, overexpression as well as loss of M6 in neurons specifically compromises long-term memory in the courtship conditioning paradigm. Our findings thus indicate a critical role of correct GPM6A/M6 levels for cognitive function and support a role of the GPM6A duplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes.


Assuntos
Colesterol/fisiologia , Transtornos Cognitivos/genética , Dosagem de Genes , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Duplicação Gênica , Humanos , Hibridização in Situ Fluorescente , Locomoção , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Comportamento Sexual Animal
13.
Hum Mutat ; 35(9): 1092-100, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924640

RESUMO

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Assuntos
Anormalidades Múltiplas/genética , Elementos Alu , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Facies , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Lactente , Masculino , Mutação , Fenótipo , RNA Mensageiro/genética , Displasia Septo-Óptica/diagnóstico , Adulto Jovem
14.
Am J Med Genet A ; 161A(5): 958-64, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23494989

RESUMO

Newborn sporadic aniridia patients with an 11p13 deletion including the WT1 gene have an increased risk to develop Wilms tumor. At present a risk for Wilms tumor cannot be estimated in patients with deletions not extending into, but ending close to WT1. Therefore, it is important to determine the distance of deletion endpoints from the WT1 gene and survey these patients for a longer follow-up time to obtain a more defined risk estimation. Using molecular methods, such as Multiplex Ligation-dependent Probe Amplification (MLPA), deletion endpoints can be mapped more accurately than with FISH. We describe here the analysis of six aniridia patients, in two of these the deletions extend close to the 3' end of WT1. At the ages of 3.8 and 4 years they have not developed a Wilms tumor, suggesting a low tumor risk in such patients. In addition we have studied 24 non-AN cases with a higher likelihood for WT1 alterations with MLPA and found no deletions. In conclusion newborns with aniridia should be studied with molecular methods that can determine deletion endpoints in 11p13 exactly. For a better Wilms tumor risk estimation cases with deletion endpoints close to WT1 should be followed for at least 4-5 years. Furthermore germ line intragenic deletions affecting WT1 in patients with a higher likelihood for a WT1 association, for example, bilateral tumors, genitourinary aberrations, or nephrotic syndrome, were not found in this study, suggesting that deletions are rare events.


Assuntos
Desequilíbrio Alélico/genética , Aniridia/genética , Cromossomos Humanos Par 11/genética , Neoplasias Renais/genética , Proteínas WT1/genética , Tumor de Wilms/genética , Pré-Escolar , Sondas de DNA , Feminino , Genes do Tumor de Wilms , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Medição de Risco , Fatores de Risco
15.
Eur J Med Genet ; 56(2): 108-13, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23220431

RESUMO

Intellectual disability (ID) is a clinically and genetically heterogeneous condition; the cause is unknown in most non-specific and sporadic cases. To establish an etiological basis in those patients represents a difficult challenge. Over the last years it has become apparent that chromosomal rearrangements below the detection level of conventional karyotyping contribute significantly to the cause of ID. We present three patients with non-specific intellectual disability who all have overlapping microdeletions in the chromosomal region 12p12.1. De novo occurrence of the deletion could be proven in the two cases from which parental samples were available. All three identified deletions have different breakpoints and range in size from 120 kb to 4.9 Mb. The smallest deletion helps to narrow down the critical region to a genomic segment (chr12:23,924,800-24,041,698, build 37/hg19) encompassing only one gene, SOX5. SOX5 is a member of the SOX (SRY-related HMG-box) family of transcription factors shown to play roles in chondroblast function, oligodendrocyte differentiation and migration, as well as ensuring proper development of specific neuronal cell types. Because of these biological functions, mutations in SOX5 are predicted to cause complex disease syndromes, as it is the case for other SOX genes, but such mutations have not yet been identified. Our findings indicate that haploinsufficiency of SOX5 is a cause of intellectual disability without any striking physical anomalies.


Assuntos
Haploinsuficiência , Deficiência Intelectual/genética , Fatores de Transcrição SOXD/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 12 , Hibridização Genômica Comparativa , Feminino , Deleção de Genes , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Masculino
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