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1.
Eur J Hum Genet ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488895

RESUMO

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

2.
Mol Genet Genomic Med ; 7(10): e00861, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414730

RESUMO

BACKGROUND: Eight different deletions and point variants of the X-chromosomal gene CNKSR2 have been reported in families with males presenting intellectual disability (ID) and epilepsy. Obligate carrier females with a frameshift variant in the N-terminal protein coding part of CNKSR2 or with a deletion of the complete gene are not affected. Only for one C-terminal nonsense variant, two carrier females were mildly affected by seizures without or with mild motor and language delay. METHODS: Exome sequencing was performed in one female child of a Dutch family, presenting seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities. Potential causative variants were validated by Sanger sequencing. X-chromosome-inactivation (XCI) analysis was performed by methylation-sensitive PCR and fragment-length analysis of the androgen-receptor CAG repeat polymorphism. RESULTS: We identified a de novo variant, c.2304G>A (p.(Trp768*)), in the C-terminal protein coding part of the X-chromosomal gene CNKSR2 in a female patient with seizures and mild ID. Sanger sequencing confirmed the presence of this nonsense variant. XCI analysis showed a mild skewing of X inactivation (20:80) in the blood of our patient. Our variant is the second C-terminal-affecting CNKSR2 variant described in neurologically affected females. CONCLUSION: Our results indicate that CNKSR2 nonsense variants in the C-terminal coding part can result in ID with seizures in female variant carriers.

3.
Am J Med Genet A ; 179(9): 1872-1877, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31207095

RESUMO

De novo pathogenic variants in the human immunodeficiency virus enhancer type I binding protein 2 (HIVEP2) gene, a large transcription factor predominantly expressed in the brain have previously been associated with intellectual disability (ID) and dysmorphic features in nine patients. We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. Exome sequencing was utilized in the investigation of the patients who had previously incurred a rigorous genetic workup for their neurodevelopmental delay, and in whom no genetic cause had been detected. Information pertaining to phenotype and genotype for new patients was collated along with data from previous reports, showing that the phenotypic spectrum of patients with HIVEP2 variants is broader than first noted. Additional characteristics are: an increased body mass index; and features of Angelman-like syndromes including: ID, limited speech, post-natal microcephaly, and hypotonia. Dysmorphic features vary between patients. As yet, no clear association between the type of gene aberration and phenotype can be concluded. HIVEP2-related ID needs to be considered in the differential diagnosis of patients with Angelman-like phenotypes and hyperphagia, and whole-exome sequencing should be considered in the genetic diagnostic armamentarium for patients with ID of inconclusive etiology.

4.
Am J Hum Genet ; 104(4): 758-766, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

5.
Genet Med ; 21(9): 2059-2069, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

6.
J Inherit Metab Dis ; 42(3): 553-564, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30746764

RESUMO

SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of N-glycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of 15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2.

8.
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.

9.
Genet Med ; 21(8): 1719-1725, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30568311

RESUMO

PURPOSE: The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance. METHODS: Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population. RESULTS: We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10-4), PPM1D (p = 4.65 × 10-2), and PHIP (p = 6.3 × 10-3). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10-2). CONCLUSION: Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.

10.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

11.
Biol Psychiatry ; 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29724491

RESUMO

BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

12.
Eur J Hum Genet ; 26(4): 552-560, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29374277

RESUMO

Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5-10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance. Linkage analysis mapped a disease locus to a 7.6 Mb candidate region on the X-chromosome (LOD score 3.3). Whole-genome sequencing identified a 2 bp insertion in exon 2 of the chromosome X open reading frame 56 gene (CXorf56), resulting in a premature stop codon. This insertion was present in all intellectually impaired individuals and carrier females. Additionally, X-inactivation status showed skewed methylation patterns favoring the inactivation of the mutated allele in the unaffected carrier females. We demonstrate that the insertion leads to nonsense-mediated decay and that CXorf56 mRNA expression is reduced in the impaired males and female. In murine brain slices and primary hippocampal neuronal cultures, CXorf56 protein was present and localized in the nucleus, cell soma, dendrites, and dendritic spines. Although no other families have been identified with pathogenic variants in CXorf56, these results suggest that CXorf56 is the causative gene in this family, and thus a novel candidate gene for X-linked ID with behavior problems.

13.
Eur J Hum Genet ; 26(1): 54-63, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29209020

RESUMO

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.

14.
Am J Hum Genet ; 101(5): 824-832, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29106825

RESUMO

The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.


Assuntos
Epilepsia/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação , Doenças do Nervo Óptico/congênito , Proteínas rab de Ligação ao GTP/genética , Adolescente , Sequência de Aminoácidos , Sítios de Ligação , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/metabolismo , Vermis Cerebelar/patologia , Criança , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/patologia , Feminino , Expressão Gênica , Guanosina Difosfato/química , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/patologia , Doenças do Nervo Óptico/diagnóstico por imagem , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Fenótipo , Ligação Proteica , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/patologia , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/deficiência
17.
PLoS Genet ; 13(7): e1006886, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28704368

RESUMO

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.


Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Cognição , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Animais , Peso Corporal , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Deleção Cromossômica , Estruturas Cromossômicas/genética , Estruturas Cromossômicas/metabolismo , Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Deleção de Genes , Rearranjo Gênico , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/genética , Proteínas Nucleares/metabolismo , Transmissão Sináptica/genética , Regulação para Cima
18.
Hum Mutat ; 38(10): 1365-1371, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28649782

RESUMO

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to ß-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.


Assuntos
Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adolescente , Criança , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Exoma , Face , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/genética , Micrognatismo/fisiopatologia , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Ligação Proteica , Fatores de Transcrição/genética
19.
PLoS Genet ; 13(3): e1006683, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346496

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Predisposição Genética para Doença/genética , Deformidades Congênitas da Mão/genética , Neoplasias Hematológicas/genética , Deficiência Intelectual/genética , Mutação , Unhas Malformadas/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Células HEK293 , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/metabolismo , Unhas Malformadas/patologia , Proteínas Nucleares/metabolismo , Fenótipo
20.
Am J Hum Genet ; 100(4): 650-658, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28343630

RESUMO

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.


Assuntos
Éxons , Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2C/genética , Adolescente , Ciclo Celular , Criança , Pré-Escolar , Humanos , Deficiência Intelectual/patologia , Adulto Jovem
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