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1.
Proc Natl Acad Sci U S A ; 117(32): 19367-19375, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719112

RESUMO

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene × gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Herança Multifatorial , Sequenciamento Completo do Exoma/métodos , Craniossinostoses/genética , Epistasia Genética , Exoma/genética , Ligação Genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos
2.
Am J Hum Genet ; 106(6): 830-845, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32442410

RESUMO

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Craniossinostoses/genética , Transtornos do Neurodesenvolvimento/genética , Osteocondroma/genética , Fatores de Transcrição SOXD/genética , Transporte Ativo do Núcleo Celular , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Pré-Escolar , Simulação por Computador , Feminino , Variação Estrutural do Genoma/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/diagnóstico , RNA-Seq , Fatores de Transcrição SOXD/química , Fatores de Transcrição SOXD/metabolismo , Síndrome , Transcrição Genética , Transcriptoma , Translocação Genética/genética
3.
BMC Med Genet ; 21(1): 90, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370745

RESUMO

BACKGROUND: ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. CASE PRESENTATION: Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. CONCLUSIONS: Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.


Assuntos
Craniossinostoses/genética , Predisposição Genética para Doença , Hipertensão Intracraniana/genética , Proteínas Repressoras/genética , Adulto , Craniossinostoses/complicações , Craniossinostoses/patologia , Craniossinostoses/cirurgia , Feminino , Heterozigoto , Humanos , Lactente , Hipertensão Intracraniana/complicações , Hipertensão Intracraniana/patologia , Hipertensão Intracraniana/cirurgia , Masculino , Mães , Crânio/patologia , Crânio/cirurgia
4.
Hum Genet ; 139(8): 1077-1090, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32266521

RESUMO

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.


Assuntos
Proteína Morfogenética Óssea 7/genética , Craniossinostoses/genética , Variação Genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Metilação de DNA , Genes Reporter , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Íntrons/genética , Desequilíbrio de Ligação , Regiões Promotoras Genéticas/genética , Fatores de Risco
5.
Plast Reconstr Surg ; 145(3): 552e-562e, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32097313

RESUMO

BACKGROUND: Several studies have verified that bone morphogenetic proteins (BMPs) may be involved in the development of craniosynostosis; little attention has been focused on the role of BMP9 in cranial suture biology. The authors investigated the role of BMP9 in suture progenitor cells. METHODS: The authors isolated and cultured prematurely fused and internal control patent suture progenitor cells from patients with nonsyndromic craniosynostosis. Overexpression of BMP9 was mediated by adenoviral vectors. Osteoblast and osteoclast differentiation-related markers were evaluated by staining techniques and touchdown quantitative polymerase chain reaction analysis. In vivo analysis of BMP9-induced suture progenitor cell osteogenesis was performed in an ectopic bone formation model. RESULTS: The authors demonstrated that the prematurely fused sutures have a higher endogenous expression of the osteogenic differentiation-related genes than patent sutures, whereas the same pattern of gene expression exists between fused and patent suture progenitor cells. Importantly, both patent and fused suture progenitor cells undergo osteogenic differentiation and express multiple lineage regulators and NELL-1 on BMP9 stimulation, whereas fused suture progenitor cells have a higher basal osteogenic potential than patent suture progenitor cells. BMP9 regulates the expression of osteoclast differentiation-related genes in suture progenitor cells. Forced BMP9 expression enhances the mineralization and maturity of ectopic bone formation of suture progenitor cells implanted in vivo. CONCLUSIONS: The authors' findings suggest that fused suture progenitor cells have elevated osteogenic potential. BMP9 could regulate the expression of multiple osteoblast and osteoclast differentiation-related genes, and NELL-1, in both suture progenitor cells, indicating that BMP9 may play a role in craniosynostosis.


Assuntos
Suturas Cranianas/patologia , Craniossinostoses/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , Proteínas de Ligação ao Cálcio/genética , Diferenciação Celular/genética , Suturas Cranianas/citologia , Suturas Cranianas/cirurgia , Craniossinostoses/patologia , Craniossinostoses/cirurgia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lactente , Masculino , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Cultura Primária de Células , Procedimentos Cirúrgicos Reconstrutivos
6.
Hum Genet ; 139(4): 461-472, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980905

RESUMO

SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.


Assuntos
Aracnodactilia , Craniossinostoses , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Síndrome de Marfan , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Adolescente , Adulto , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Aracnodactilia/metabolismo , Criança , Pré-Escolar , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Craniossinostoses/metabolismo , Feminino , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Pessoa de Meia-Idade , Patologia Molecular
7.
Anim Genet ; 51(1): 127-131, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31774195

RESUMO

Missense variants are associated with various phenotypic traits and disorders in dogs. The canine P2RX7 gene, coding the ATP-gated P2X7 receptor ion channel, contains four known missense variants. The current study aimed to examine the presence of these variants in a random sample of pedigree and mixed-pedigree dogs. Exons 3, 8, 11 and 13 of the P2RX7 gene, encoding these four respective variants, in 65 dogs were assessed by Sanger sequencing and combined with existing sequencing data from another 69 dogs. The distribution of these variants was then evaluated in all 134 dogs combined and separately within individual breeds including 35 different pure breeds. The rs23314713 (p.Phe103Leu) and rs23315462 (p.Pro452Ser) variants were present in 47 and 40% of all dogs studied respectively, with the rs23314713 variant associated with brachycephalic breeds. Among pedigree dogs, the rs23314713 and rs23315462 variants were associated with brachycephalic and non-brachycephalic breeds respectively. The rs851148233 (p.Arg270Cys) and rs850760787 (p.Arg365Gln) variants were present only in dogs of Cocker Spaniel and Labrador Retriever pedigrees respectively. No other missense variants were found in exons 3, 8, 11 and 13 of the P2RX7 gene within the dogs. In conclusion, the rs23314713 and rs23315462 missense variants of the P2RX7 gene are present in a large proportion of dogs, with the rs23314713 variant associated with a number of brachycephalic breeds. However, the association of this variant with dogs of bulldog ancestry, not brachycephaly per se, cannot be excluded.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Mutação de Sentido Incorreto , Receptores Purinérgicos P2X7/genética , Animais , Cruzamento , Craniossinostoses/genética , Linhagem
8.
J Craniofac Surg ; 31(1): 283-285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31764566

RESUMO

The aims of this retrospective case series were to investigate whether twins born with craniosynostosis mirrored each other regarding operative surgery performed, age of undertaking surgery; outcomes in speech, language, and developmental milestones and what environmental factors were present for each set of twins.Case selection was based on clinical and radiographical evidence of craniosynostosis amongst twin sets. The twin sets included were those with craniosynostosis who had different sutures affected or those with the same suture affected but with a varying degree of severity.The presence of the following factors may have played an influential role in the clinical presentation of the twins; these were as follows: a maternal history of smoking, breech presentation, and genetic mutations. It was notable that the overall outcomes for the twins in this study were similar.These cases highlight the multifactorial nature in the development of craniosynostosis and how this influenced the phenotypic presentation of the twins.


Assuntos
Craniossinostoses/genética , Epigênese Genética , Feminino , Nível de Saúde , Humanos , Lactente , Masculino , Gravidez , Estudos Retrospectivos , Fumar , Gêmeos
9.
J Dent Res ; 99(2): 223-232, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31869252

RESUMO

Premature fusion of the cranial suture and midface hypoplasia are common features of syndromic craniosynostosis caused by mutations in the FGFR2 gene. The only treatment for this condition involves a series of risky surgical procedures designed to correct defects in the craniofacial bones, which must be performed until brain growth has been completed. Several pharmacologic interventions directed at FGFR2 downstream signaling have been tested as potential treatments for premature coronal suture fusion in a mouse model of Apert syndrome. However, there are no published studies that have targeted for the pharmacologic treatment of midface hypoplasia. We used Fgfr2S252W/+ knock-in mice as a model of Apert syndrome and morphometric analyses to identify causal hypoplastic sites in the midface region. Three-dimensional geometric and linear analyses of Fgfr2S252W/+ mice at postnatal day 0 demonstrated distinct morphologic variance. The premature fusion of anterior facial bones, such as the maxilla, nasal, and frontal bones, rather than the cranium or cranial base, is the main contributing factor toward the anterior-posterior skull length shortening. The cranial base of the mouse model had a noticeable downward slant around the intersphenoid synchondrosis, which is related to distortion of the airway. Within a skull, the facial shape variance was highly correlated with the cranial base angle change along Fgfr2 S252W mutation-induced craniofacial anomalies. The inhibition of an FGFR2 downstream signaling enzyme, PIN1, via genetic knockdown or use of a PIN1 inhibitor, juglone, attenuated the aforementioned deformities in a mouse model of Apert syndrome. Overall, these results indicate that FGFR2 signaling is a key contributor toward abnormal anterior-posterior dimensional growth in the midface region. Our study suggests a novel therapeutic option for the prevention of craniofacial malformations induced by mutations in the FGFR2 gene.


Assuntos
Acrocefalossindactilia , Craniossinostoses , Peptidilprolil Isomerase de Interação com NIMA , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Acrocefalossindactilia/genética , Animais , Suturas Cranianas , Craniossinostoses/genética , Modelos Animais de Doenças , Face , Camundongos , Peptidilprolil Isomerase de Interação com NIMA/fisiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/fisiologia
10.
Clin Dysmorphol ; 29(1): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31609728

RESUMO

Muenke syndrome is a craniosynostosis syndrome associated with the p.Pro250Arg mutation in FGFR3. An increasing number of individuals with this mutation are reported to not have craniosynostosis. The purpose of this report is to increase awareness of the high phenotypic variability seen in Muenke syndrome. DNA testing for the p.Pro250Arg mutation is routinely performed in Denmark, in children presenting with isolated coronal synostosis. Verified diagnosis entails detailed family history, drawing of family pedigree, DNA testing of the parents, genetic counseling, skull radiographs, clinical photographs, and follow-up. Sixteen individuals from 5 Danish families with Muenke syndrome are presented. Large phenotypic variation was seen both within and across families. The most striking observations were that 6/16 (38%) cases did not have craniosynostosis and one individual presented with a normal phenotype. In addition, 3 unrelated cases had incomplete cleft palate, submucous cleft palate, and bifid uvula, respectively. There is strong evidence for reduced penetrance of the craniosynostosis trait in Muenke syndrome. We argue that many studies on Muenke syndrome have been influenced by ascertainment bias in regard to craniosynostosis. In addition, it is suggested that oral clefting might be part of the clinical spectrum seen in Muenke syndrome.


Assuntos
Craniossinostoses , Família , Mutação de Sentido Incorreto , Linhagem , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Substituição de Aminoácidos , Criança , Pré-Escolar , Craniossinostoses/genética , Craniossinostoses/patologia , Dinamarca , Feminino , Seguimentos , Humanos , Lactente
11.
Plast Reconstr Surg ; 145(1): 117e-125e, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31592950

RESUMO

BACKGROUND: De novo or rare transmitted mutations in the SMAD6 gene affect 7 percent of midline nonsyndromic synostosis patients. This study aimed to determine the neurocognitive sequelae of SMAD6 synostosis. METHODS: Nonsyndromic synostosis patients 6 years or older with SMAD6 mutations and non-SMAD6 nonsyndromic synostosis controls were recruited. All patients completed a double-blinded neurodevelopmental battery (i.e., Wechsler Fundamentals, Wechsler Abbreviated Scale of Intelligence, Beery-Buktenica Developmental test), and parents/guardians completed behavioral surveys (Behavior Rating Inventory of Executive Function and Behavior Rating System for Children). RESULTS: Twenty-eight patients participated: 10 known SMAD6 patients (average age, 10 years; 1 female; eight metopic and two sagittal; nine treated with cranial vault remodeling and one treated with strip craniectomy) and 18 non-SMAD6 controls (age, 9.5 years; three female; 12 metopic and six sagittal; 17 treated with cranial vault remodeling and one treated with strip craniectomy). There were no differences between any demographics. Testing age, surgical age, parental education, and household income correlated with cognition (p < 0.05). After controlling for these factors, SMAD6 patients performed worse on numerical operations (p = 0.046), performance intelligence quotient (p = 0.018), full-scale intelligence quotient (p = 0.010), and motor coordination (p = 0.043) compared to age/race/gender/synostosis/operation-matched controls. On behavioral surveys, SMAD6 patients scored worse on 14 assessments, including aggression, communication, and behavior. CONCLUSIONS: This prospective double-blinded study revealed that neuropsychiatric development of nonsyndromic synostosis may be under genetic control. SMAD6 mutations led to poorer mathematics, performance intelligence quotient, full-scale intelligence quotient, and motor coordination, even after controlling for exogenous factors. Genetic testing may be critical for advocating early adjunctive neurodevelopmental therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.


Assuntos
Craniossinostoses/cirurgia , Craniotomia/métodos , Deficiências do Desenvolvimento/genética , Procedimentos Cirúrgicos Reconstrutivos/métodos , Proteína Smad6/genética , Estudos de Casos e Controles , Criança , Comportamento Infantil , Desenvolvimento Infantil , Pré-Escolar , Craniossinostoses/complicações , Craniossinostoses/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/prevenção & controle , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactente , Testes de Inteligência , Mutação com Perda de Função , Masculino , Estudos Prospectivos , Crânio/cirurgia , Resultado do Tratamento
12.
Eur J Med Genet ; 63(2): 103652, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30986546

RESUMO

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by the triad of short stature, microtia and absent or small patellae. We report on a patient with MGS secondary to biallelic mutations in CDC45 detected on whole exome sequencing (WES). Patients with MGS caused by mutations in CDC45 display a distinct phenotype characterized by craniosynostosis and anorectal malformation. Our patient had craniosynostosis, anorectal malformation and short stature, but did not have the microtia or patella hypoplasia. Our report also highlights the value of WES in aiding diagnosis of patients with rare genetic diseases. In conclusion, our case report and review of the literature illustrates the unique features of CDC45-related MGS as well as the benefits of WES in reducing the diagnostic odyssey for patients with rare genetic disorders.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/diagnóstico , Microtia Congênita/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Micrognatismo/diagnóstico , Micrognatismo/genética , Patela/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Malformações Anorretais/genética , Malformações Anorretais/fisiopatologia , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Feminino , Transtornos do Crescimento/congênito , Humanos , Mutação , Fenótipo , Doenças Raras/genética , Doenças Raras/fisiopatologia , Sequenciamento Completo do Exoma
13.
Eur J Med Genet ; 63(1): 103637, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30858058

RESUMO

Xia-Gibbs syndrome (Mental retardation, autosomal dominant 25; MRD25) [MIM 615829] is a rare autosomal dominant disease characterized by mental retardation, developmental delay, speech delay, structural brain anomalies, hypotonicity, protuberant eyes, visual problems, laryngomalacia and snoring. Since the first description in 2014, fewer than 50 patients with Xia-Gibbs syndrome have been noticed in the literature. We describe here 2 years 2 months old girl with developmental delay, brain anomalies, laryngomalacia and craniosynostosis. Whole-Exome Sequencing (WES) analyses in patient showed a heterozygous NM_001029882: c.4370 A>G; p. (Asp1457Gly) mutation in AHDC1. Craniosynostosis rarely observed in the patients described to date, and west syndrome-like EEG pattern, constipation and electrolyte imbalance observed for the first time were present in our patient. Further reports and in-vivo/in-vitro works will make possible knowing of the genetic and clinical background of this disease.


Assuntos
Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Craniossinostoses/patologia , Exoma/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/patologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia
14.
Anim Genet ; 51(1): 122-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691328

RESUMO

A GWAS was performed for inborn X-linked facial dysmorphia with severe growth retardation in Labrador Retrievers. This lethal condition was mapped on the X chromosome at 17-21 Mb and supported by eight SNPs in complete LD. Dams of affected male puppies were heterozygous for the significantly associated SNPs and male affected puppies carried the associated alleles hemizygously. In the near vicinity to the associated region, RPS6KA3 was identified as a candidate gene causing facial dysmorphia in humans and mice known as Coffin-Lowry syndrome. Haplotype analysis showed significant association with the phenotypes of all 18 animals under study. This haplotype was validated through normal male progeny from a dam with the not-associated haplotype on both X chromosomes but male affected full-sibs with the associated haplotype.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Genes Letais , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Craniossinostoses/genética , Feminino , Estudos de Associação Genética/veterinária , Haplótipos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética
15.
PLoS One ; 14(12): e0226280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31841527

RESUMO

Brachycephalic syndrome (BS) is a pathophysiological disorder caused by excessive soft tissue within the upper airways of short-nosed dog breeds, causing obstruction of the nasal, pharyngeal and laryngeal lumen, resulting in severe respiratory distress. As the prevalence of BS appears to be high among some of the affected breeds, there is an urgent need for breeding efforts to improve the health status of those dogs. In the present study, we evaluated correlations between morphometric and other phenotypic characteristics and BS in a population of 69 French bulldogs from Denmark to identify parameters that could serve as a basis for breeding against BS. Furthermore, the genetic variation was monitored to determine whether it would be possible to breed based on these characteristics without simultaneously causing a critical reduction in genetic variation. Six phenotypic characteristics were correlated with the Brachycephalic Syndrome Functional (BSF) score. Among the morphometric risk factors, nostril stenosis (NS) and neck girth (NG) had the highest impact on the BSF score, accounting for 32% and 4% of the variation, respectively. The genetic variation in the population was comparable to other pure breeds, i.e. estimated and observed heterozygosity was 0.60 and the average inbreeding coefficient was 0.01. If only dogs with Grades 1 and 2 NS (no or only mild NS) were selected for breeding the mean BSF score would be reduced significantly. However, it would result in the exclusion of 81% of the population for breeding and this is not prudent. Excluding only dogs with severe stenosis (Grade 4) would exclude 50% of the population without any adverse impact on genetic variation within the population. Although exclusion of dogs with Grade 4 would result in an apparent reduction in the mean BSF score, this reduction is not significant. As NS accounts for 32% of the variation in BSF score, a possible long term strategy to reduce the prevalence of the BS in French bulldogs would seem to be a selection scheme that first excluded dogs with the most severe NS from breeding, gradually moving towards selecting dogs with lower NS grades. According to our findings there is no viable short term solution for reducing the prevalence of BS in the French bulldog population.


Assuntos
Obstrução das Vias Respiratórias/prevenção & controle , Cruzamento/métodos , Craniossinostoses/prevenção & controle , Doenças do Cão/prevenção & controle , Cães , Respiração , Obstrução das Vias Respiratórias/genética , Animais , Craniossinostoses/complicações , Craniossinostoses/genética , Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/anatomia & histologia , Teste de Esforço/veterinária , Feminino , Masculino , Cavidade Nasal/anatomia & histologia , Cavidade Nasal/fisiopatologia , Fenótipo , Respiração/genética , Fatores de Risco , Seleção Genética/fisiologia , Síndrome
16.
J Genet ; 982019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31819025

RESUMO

Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype-phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring-Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in ASXL1 mutation carriers.


Assuntos
Craniossinostoses/genética , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Mutação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sequência de Bases , Encéfalo/diagnóstico por imagem , Criança , Códon sem Sentido/genética , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/fisiopatologia , Feminino , Estudos de Associação Genética , Doenças Genéticas Inatas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Hipotonia Muscular , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
17.
J Neurosurg Pediatr ; 24(6): 622-631, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786542

RESUMO

BACKGROUND: Craniosynostosis is a condition in which 2 or more of the skull bones fuse prematurely. The spectrum of the disorder most commonly involves the closure of a single suture in the skull, but it can also involve syndromic diagnoses in which multiple skull bones and/or bones outside of the cranium are affected. Craniosynostosis can result in cosmetic deformity as well as potential limitations in brain growth and development, and the neurocognitive impact of the condition is just starting to be studied more thoroughly. Our knowledge regarding the genetics of this condition has also evolved substantially. In this review, the authors explore the medical and surgical advancements in understanding and treating this condition over the past century, with a focus on how the diagnosis and treatment have evolved. METHODS: In this review article, the authors, who are the leaders of a craniofacial team at a major academic pediatric hospital, focus on single-suture craniosynostosis (SSC) affecting the 6 major cranial sutures and discuss the evolution of the treatment of SSC from its early history in modern medicine through the current state of the art and future trends. This discussion is based on the authors' broad experience and a comprehensive review of the literature. SUMMARY: The management of SSC has evolved substantially over the past 100 years. There have been major advances in technology and medical knowledge that have allowed for safer treatment of this condition through the use of newer techniques and technologies in the fields of surgery, anesthesia, and critical care. The use of less invasive surgical techniques along with other innovations has led to improved outcomes in SSC patients. The future of SSC treatment will likely be guided by elucidation of the causes of neurocognitive delay in these children and assessment of how the timing and type of surgery can mitigate adverse outcomes.


Assuntos
Craniossinostoses/cirurgia , Procedimentos Neurocirúrgicos/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Disfunção Cognitiva/etiologia , Suturas Cranianas , Craniossinostoses/complicações , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Deficiências do Desenvolvimento/etiologia , Humanos , Neuroendoscopia/métodos , Aparência Física , Fatores de Tempo
18.
Neurochirurgie ; 65(5): 196-201, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31605683

RESUMO

Craniosynostosis (CS) is defined as the premature fusion of cranial sutures, leading to an abnormal skull shape. The overall incidence is between 1: 2,000 and 1: 3,000 live births. Genetic causes are found in 20% of cases. CS can be isolated (non-syndromic CS/NSCS) or they can be part of multiple congenital abnormalities syndromes (syndromic CS/SCS). A few SCS, such as Crouzon, Pfeiffer, Apert and Saethre-Chotzen syndromes, are very well known and their molecular bases have been clarified in the 90s and early 2000s, thus showing the major role of the FGF receptors and TWIST signaling pathways in the etiology of these conditions. The recent availability of powerful molecular tools for genetic diagnosis, such as whole exome or whole genome sequencing, has led to the characterization of the molecular bases of an increasing number of CS, thus emphasizing the significant genetic heterogeneity of these conditions, and blurring the limit between SCS and NSCS. The genetic characterization of patients affected by CS leads to appropriate genetic counseling and provides relevant information concerning comorbidity and prognosis. Nevertheless, this can also lead to the detection of susceptibility factors with low penetrance whose interpretation in genetic counseling is difficult and it raises the question of its cost-effectiveness for health systems. These aspects suggest the need of a patient-tailored clear rationale for performing genetic tests. In this study, we reviewed the main molecular etiologies reported in the last 15 years of either SCS or NSCS, and we propose a systematic multidisciplinary approach as well as a diagnostic flowchart for the genetic evaluation of these patients.


Assuntos
Craniossinostoses/genética , Adulto , Craniossinostoses/diagnóstico , Testes Genéticos , Humanos , Recém-Nascido , Síndrome
19.
Neurochirurgie ; 65(5): 246-251, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568780

RESUMO

INTRODUCTION: The aim of this review was to report on recent advances in trigonocephaly since the last report on craniosynostosis published in 2006. MATERIAL AND METHODS: The review was conducted in accordance with the PRISMA guidelines. Research focused on four main topics: epidemiology, neurodevelopmental disorders, genetics and surgical techniques. RESULTS: Forty reports were included. The prevalence of trigonocephaly increased during the last two decades both in Europe and in the United States, but no clear contributing factors have yet been identified. Neurodevelopmental disorders are frequent in syndromic trigonocephaly and not particularly rare in non-syndromic cases (up to 34%). Developmental retardation (speech, motor or global) was almost always present in children exposed to valproic acid. Chromosomal abnormalities described in metopic synostosis comprised deletion of chromosome 11q24, deletion or trisomy of 9p and deletion of 7p, deletions of 3q, 13q, 12pter, 22q11, and duplication of 15q25. SMAD6 mutations should be systematically screened for in familial cases. Recent advances in surgical techniques have mainly concerned endoscopic-assisted procedures, as they significantly reduce perioperative morbidity. CONCLUSIONS: Neurosurgeons, maxillofacial and plastic surgeons will be increasingly concerned with trigonocephaly because of the increase in prevalence observed over the last two decades. Cytogenetic alterations are probably underestimated in this craniosynostosis, considering the high rate of neurodevelopmental retardation compared to other single-suture synostoses. Genetic counselling is therefore more and more effective in this pathology. An objective method to evaluate the cosmetic results of both endoscopic and open surgeries is necessary, as some under-corrections have been reported with minimally invasive surgery.


Assuntos
Craniossinostoses/cirurgia , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Craniossinostoses/epidemiologia , Craniossinostoses/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual , Programas de Rastreamento , Procedimentos Cirúrgicos Reconstrutivos , Ácido Valproico/efeitos adversos
20.
Neurochirurgie ; 65(5): 202-209, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563616

RESUMO

BACKGROUND: Various animal models mimicking craniosynostosis have been developed, using mutant zebrafish and mouse. The aim of this paper is to review the different animal models for syndromic craniosynostosis and analyze what insights they have provided in our understanding of the pathophysiology of these conditions. MATERIAL AND METHODS: The relevant literature for animal models of craniosynostosis was reviewed. RESULTS: Although few studies on craniosynostosis using zebrafish were published, this model appears useful in studying the suture formation mechanisms conserved across vertebrates. Conversely, several mouse models have been generated for the most common syndromic craniosynostoses, associated with mutations in FGFR1, FGFR2, FGFR3 and TWIST genes and also in MSX2, EFFNA, GLI3, FREM1, FGF3/4 genes. The mouse models have also been used to test pharmacological treatments to restore craniofacial growth. CONCLUSIONS: Several zebrafish and mouse models have been developed in recent decades. These animal models have been helpful for our understanding of normal and pathological craniofacial growth. Mouse models mimicking craniosynostoses can be easily used for the screening of drugs as therapeutic candidates.


Assuntos
Craniossinostoses/patologia , Modelos Animais de Doenças , Animais , Craniossinostoses/genética , Humanos , Mutação
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