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1.
Am J Med Genet A ; 179(10): 2075-2082, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361404

RESUMO

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

2.
Am J Hum Genet ; 104(5): 914-924, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982611

RESUMO

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

3.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
4.
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.

5.
Eur J Hum Genet ; 25(10): 1126-1133, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28905882

RESUMO

Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Δ) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Δ promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Δ)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia.


Assuntos
Atresia das Cóanas/genética , Surdez/congênito , Deleção de Genes , Cardiopatias Congênitas/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Atresia das Cóanas/diagnóstico , Surdez/diagnóstico , Surdez/genética , Facies , Feminino , Cardiopatias Congênitas/diagnóstico , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Regiões Promotoras Genéticas
6.
Am J Med Genet A ; 2017 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-28498556

RESUMO

Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.

7.
Am J Med Genet A ; 2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-28513979

RESUMO

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here.

8.
Front Behav Neurosci ; 11: 248, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29311865

RESUMO

KBG syndrome is a neurodevelopmental disorder (NDD) caused by loss-of-function of the ANKRD11 gene. The core phenotype comprises developmental delay (DD)/ intellectual disability (ID) and several specific facial dysmorphisms. In addition, both ADHD- and ASD-related symptoms have been mentioned. For the correct understanding of these developmental and behavioral characteristics however, it is of great importance to apply objective measures, which seldom has been done in patients with KBG syndrome. In this study, intelligence profiles of patients with KBG syndrome (n = 18) were compared with a control group comprising patients with NDD caused by various other genetic defects (n = 17), by means of the Wechsler scales. These scales were also used to measure speed of information processing, working memory, verbal comprehension and perceptual reasoning. No significant differences were found in the global level of intelligence of patients with KBG syndrome as compared to the patient genetic control group. The same was true for Wechsler subtest results. Hence, behavioral problems associated with KBG syndrome cannot directly be related to or explained by a specific intelligence profile. Instead, specific assessment of neurocognitive functions should be performed to clarify the putative behavioral problems as observed in this syndrome.

10.
Am J Hum Genet ; 98(3): 541-552, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942287

RESUMO

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Transposases/genética , Adolescente , Adulto , Animais , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Regulação para Baixo , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Exoma , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Modelos Lineares , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
11.
Genet Med ; 18(11): 1158-1162, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26963285

RESUMO

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.


Assuntos
Anodontia/genética , Exoma/genética , Predisposição Genética para Doença , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Adolescente , Anodontia/patologia , Criança , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Análise de Sequência de DNA , Via de Sinalização Wnt/genética
12.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
13.
Am J Hum Genet ; 97(3): 493-500, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26340335

RESUMO

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Cromossômicas não Histona/genética , Códon sem Sentido/genética , Deficiência Intelectual/genética , Fosfoproteínas/genética , Distúrbios da Fala/genética , Sequência de Bases , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA
15.
Eur J Ophthalmol ; 25(4): e46-9, 2015 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-25655594

RESUMO

PURPOSE: Primary cataract is often the initial manifestation of the adult-onset type of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. It is caused by a CTG repeat expansion within the DMPK gene, and anticipation may cause earlier onset and more severe symptoms in subsequent generations. METHODS: We report a family with hereditary cataract, which was initially classified as primary hereditary cataract. After presentation of 2 children with motor development delay and behavioral changes, DM1 was diagnosed. Subsequently, various DM1 features were recognized in older family members. CONCLUSIONS: This report aims to increase awareness among ophthalmologists of the high prevalence of DM1 among young primary cataract patients. Ophthalmologists can play a significant role in early diagnosis, since cataract frequently is the first occasion that patients seek medical attention. Early recognition is crucial since it enables adequate cardiac follow-up and allows counseling of couples of childbearing age.


Assuntos
Catarata/diagnóstico , Distrofia Miotônica/diagnóstico , Adulto , Extração de Catarata , Criança , Feminino , Humanos , Implante de Lente Intraocular , Masculino , Linhagem , Adulto Jovem
16.
Eur J Hum Genet ; 23(9): 1176-85, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25424714

RESUMO

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Doenças do Desenvolvimento Ósseo/genética , Cromossomos Humanos Par 16 , Deleção de Genes , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/patologia , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Exoma , Facies , Feminino , Expressão Gênica , Genótipo , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Anormalidades Dentárias/complicações , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/patologia
17.
Eur J Hum Genet ; 22(9): 1063-70, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24398796

RESUMO

This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology.


Assuntos
Deformidades Dentofaciais/genética , Mutação , Linhagem , Proteínas Wnt/genética , Adulto , Anodontia/diagnóstico , Anodontia/genética , Criança , Pré-Escolar , Deformidades Dentofaciais/diagnóstico , Glândulas Écrinas/anormalidades , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/genética , Feminino , Variação Genética , Genótipo , Humanos , Hipotricose/diagnóstico , Hipotricose/genética , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Masculino , Fenótipo
18.
Arch Dis Child ; 99(1): 52-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24146286

RESUMO

OBJECTIVE: To review the clinical and molecular-genetic characteristics of 34 children who were referred to the clinical genetics department with a presenting diagnosis of definite or suspected velopharyngeal insufficiency (VPI, defined as the inability to close off the nasal from the oral cavity during speech) or hyponasal/hypernasal speech. All the patients referred also had additional anomalies and did not therefore comprise the whole VPI population. METHODS: Patients were clinically investigated by a clinical geneticist. Fluorescent in situ hybridisation for chromosome 22q11 deletion and/or array comparative genomic hybridisation (array CGH) analysis was performed in all cases. A literature review was performed using the Pubmed online database. RESULTS: Microdeletions or microduplications were identified in half of the patients. Six patients (∼18% of total) carried a chromosome 22q11 microdeletion, one patient had a chromosome 22q11 microduplication, and four patients had microdeletions in other chromosomes that were considered likely to be associated with the phenotype. One patient had KBG syndrome. Thus, an underlying genetic abnormality was found in approximately one-third (35%) of our patients. An additional seven patients harboured copy number variations that were considered benign or of unknown significance. CONCLUSIONS: We present an overview of patients with VPI or hyponasal/hypernasal speech with additional anomalies and their clinical and genetic findings. In one-third of these patients, an underlying genetic abnormality was identified. This has important implications for family counselling and medical follow-up. Furthermore, we recommend array CGH testing in all patients with VPI and associated anomalies because of the high percentage of copy number variants identified in these patients.


Assuntos
Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Distúrbios da Fala/etiologia , Insuficiência Velofaríngea/genética , Criança , Deleção Cromossômica , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Insuficiência Velofaríngea/complicações
19.
J Med Genet ; 50(12): 802-11, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24123876

RESUMO

BACKGROUND: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. OBJECTIVES: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. METHODS AND RESULTS: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. CONCLUSIONS: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.


Assuntos
Exoma/genética , Deficiência Intelectual/genética , Mutação/genética , Análise Mutacional de DNA , Família , Feminino , Humanos , Masculino , Linhagem
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