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2.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

3.
Am J Hum Genet ; 104(1): 139-156, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372

RESUMO

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

4.
Haemophilia ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30431218

RESUMO

INTRODUCTION: Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. AIM: To describe the phenotype and genetic profile of patients with a bleeding tendency. METHODS: Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. RESULTS: Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. CONCLUSION: Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.

5.
Nat Genet ; 48(8): 877-87, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399968

RESUMO

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.


Assuntos
Córtex Cerebral/patologia , Haploinsuficiência/genética , Deficiência Intelectual/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação/genética , Neurogênese/fisiologia , Proteínas Repressoras/genética , Anormalidades Múltiplas , Adolescente , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Animais , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Proteínas Repressoras/metabolismo , Síndrome , Adulto Jovem
6.
J Med Genet ; 53(8): 523-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27075013

RESUMO

BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.


Assuntos
Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas/genética , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Haploinsuficiência/genética , Humanos , Lactente , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Deleção de Sequência/genética , Síndrome , Adulto Jovem
7.
Am J Hum Genet ; 97(6): 904-13, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26637980

RESUMO

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.


Assuntos
Microtia Congênita/genética , Nanismo/genética , Geminina/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Patela/anormalidades , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Ciclo Celular/genética , Pré-Escolar , Microtia Congênita/metabolismo , Nanismo/metabolismo , Nanismo/patologia , Éxons , Feminino , Geminina/metabolismo , Expressão Gênica , Genes Dominantes , Transtornos do Crescimento/metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Padrões de Herança , Masculino , Micrognatismo/metabolismo , Dados de Sequência Molecular , Patela/metabolismo , Linhagem , Estabilidade Proteica , Proteólise , Processamento de RNA , Alinhamento de Sequência
8.
Orphanet J Rare Dis ; 10: 114, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26381604

RESUMO

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.


Assuntos
Microtia Congênita/diagnóstico , Microtia Congênita/terapia , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/terapia , Micrognatismo/diagnóstico , Micrognatismo/terapia , Patela/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Microtia Congênita/genética , Feminino , Transtornos do Crescimento/genética , Humanos , Masculino , Micrognatismo/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/terapia
9.
Hum Mutat ; 36(1): 69-78, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25265257

RESUMO

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.


Assuntos
Transtornos Cognitivos/genética , Cinesina/química , Cinesina/genética , Doenças do Sistema Nervoso/genética , Paraparesia Espástica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Transtornos Cognitivos/patologia , Epilepsia/genética , Epilepsia/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/patologia , Paraparesia Espástica/patologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Estrutura Terciária de Proteína , Adulto Jovem
10.
Eur J Hum Genet ; 23(6): 803-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25205402

RESUMO

AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.


Assuntos
Deleção de Genes , Deficiência Intelectual/genética , Microcefalia/genética , Polimorfismo Genético , Proteínas/genética , Éxons , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome , Adulto Jovem
11.
Eur J Hum Genet ; 22(6): 844-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24193349

RESUMO

The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Códon sem Sentido , Proteínas Repressoras/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Análise Mutacional de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Humanos , Lactente , Síndrome
12.
Am J Med Genet A ; 158A(11): 2733-42, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23023959

RESUMO

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.


Assuntos
Gráficos de Crescimento , Transtornos do Crescimento/diagnóstico , Micrognatismo/diagnóstico , Desenvolvimento Sexual , Proteínas de Ciclo Celular/genética , Pré-Escolar , Estudos de Coortes , Microtia Congênita , Orelha/anormalidades , Feminino , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Lactente , Masculino , Micrognatismo/tratamento farmacológico , Micrognatismo/genética , Mutação , Complexo de Reconhecimento de Origem/genética , Patela/anormalidades , Desenvolvimento Sexual/genética , Anormalidades Urogenitais
13.
Eur J Hum Genet ; 20(6): 598-606, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22333897

RESUMO

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.


Assuntos
Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Micrognatismo/diagnóstico , Micrognatismo/genética , Mutação , Complexo de Reconhecimento de Origem/genética , Adolescente , Adulto , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Microtia Congênita , Orelha/anormalidades , Feminino , Estudos de Associação Genética , Transtornos do Crescimento/metabolismo , Humanos , Lactente , Masculino , Micrognatismo/metabolismo , Pessoa de Meia-Idade , Patela/anormalidades , Patela/metabolismo
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