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2.
Int J Psychol ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31245844

RESUMO

A recent re-operationalisation of grandiose narcissism has resulted in the distinction of two narcissistic strategies based on the cognitive, affective-motivational and behavioural dynamics: admiration (assertive self-enhancement) and rivalry (antagonistic self-protection). The Narcissistic Admiration and Rivalry Questionnaire (NARQ) was developed to assess this model with two higher-order dimensions. However, cross-validations of the NARQ have not been extensively conducted across diverse population groups and languages. This study aimed to test the internal and external validity (through the relation with envy and self-esteem), reliability and cross-cultural equivalence of the Spanish version of the NARQ. The psychometric properties were evaluated in a Spanish sample (N = 310), and cross-cultural equivalence was tested in participants from Chile (N = 234) and Colombia (N = 256). The results supported the reliability and validity of the Spanish NARQ, as well as the cross-cultural equivalence across Spanish-speaking countries. In addition, we discuss obtained differences across Spanish, Chilean and Colombian sample within two narcissistic strategies.

3.
J Med Genet ; 56(9): 590-601, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31010831

RESUMO

BACKGROUND: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of ß-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing. METHODS: Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients. RESULTS: Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before. CONCLUSION: Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.

4.
Eur J Hum Genet ; 27(4): 525-534, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30622331

RESUMO

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

5.
Linacre Q ; 85(1): 49-62, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29970937

RESUMO

Infant male circumcision (IMC) has become controversial among Catholics, and many have criticized the practice of routine IMC, still widely performed in the United States. Others have gone further, claiming that circumcision has been condemned explicitly by the Church and criticizing IMC as "mutilation" and, hence, prohibited implicitly by Catholic moral principles. However, closer examination of the Catholic tradition shows that the Church regards IMC as having been a means of grace under the Old Covenant and, more importantly, in the flesh of Jesus. This positive theological account of IMC cannot be evaded by invoking a supposed historical distinction between milah (a token cut) and periah (the complete removal of the foreskin). The Church has never condemned IMC as mutilation, and while IMC carries some risk, there is no evidence that it inflicts per se disabling mutilation. A reasonable body of medical opinion regards IMC as conferring net health benefits. Summary: This paper concerns the ethics of infant male circumcision especially, though not only, as this is practiced within contemporary Judaism. This topic is examined from a Catholic ethical and theological perspective. It is found that the Church has never sought to restrict Jews from practicing circumcision and has never condemned circumcision as "mutilation." Current evidence suggests that infant male circumcision confers net health benefits. Catholic theology since the Second Vatican Council has increasingly emphasized that God's covenant with the Jewish people remains valid. It has never been revoked. This covenant includes infant male circumcision.

6.
J Med Genet ; 55(6): 359-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29618507

RESUMO

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

7.
Am J Med Genet A ; 176(7): 1614-1617, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29704302

RESUMO

Ankyloglossia is a congenital oral anomaly characterized by the presence of a hypertrophic and short lingual frenulum. Mutations in the gene encoding the transcription factor TBX22 have been involved in isolated ankyloglossia and X-linked cleft palate. The knockout of Lgr5 in mice results in ankyloglossia. Here, we report a five-generation family including patients with severe ankyloglossia and missing lower central incisors. Two members of this family also exhibited congenital anorectal malformations. In this report, male-to-male transmission was in favor of an autosomal dominant inheritance, which allowed us to exclude the X-linked TBX22 gene. Linkage analysis using short tandem repeat markers located in the vicinity of LGR5 excluded this gene as a potential candidate. These results indicate genetic heterogeneity for ankyloglossia. Further investigations with additional families are required in order to identify novel candidate genes.

8.
NPJ Genom Med ; 2: 32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263841

RESUMO

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

9.
Mol Syndromol ; 8(4): 172-178, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28690482

RESUMO

Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the TWIST2 gene. Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning. We studied the impact that the presence of BSS and AMS has on psychosocial functioning of affected individuals and their families, using their point of view to start with. We tabulated frequently asked questions from affected individuals and families, and a parent of an affected child and an affected adult woman offered personal testimonies. We focused on perception of illness, body satisfaction, and the consequences for an otherwise normal individual who has a disorder that interferes with body image. The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves.

10.
Environ Toxicol Chem ; 36(12): 3223-3231, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28727171

RESUMO

In a recent scientific opinion of the European Food Safety Authority it is argued that the accumulation of plant protection products in sediments over long time periods may be an environmentally significant process. Therefore, the European Food Safety Authority proposed a calculation to account for plant protection product accumulation. This calculation, however, considers plant protection product degradation within sediment as the only dissipation route, and does not account for sediment dynamics or back-diffusion into the water column. The hydraulic model Hydrologic Engineering Center-River Analysis System (HEC-RAS; US Army Corps of Engineers) was parameterized to assess sediment transport and deposition dynamics within the FOrum for Co-ordination of pesticide fate models and their USe (FOCUS) scenarios in simulations spanning 20 yr. The results show that only 10 to 50% of incoming sediment would be deposited. The remaining portion of sediment particles is transported across the downstream boundary. For a generic plant protection product substance this resulted in deposition of only 20 to 50% of incoming plant protection product substance. In a separate analysis, the FOCUS TOXSWA model was utilized to examine the relative importance of degradation versus back-diffusion as loss processes from the sediment compartment for a diverse range of generic plant protection products. In simulations spanning 20 yr, it was shown that back-diffusion was generally the dominant dissipation process. The results of the present study show that sediment dynamics and back-diffusion should be considered when calculating long-term plant protection product accumulation in sediment. Neglecting these may lead to a systematic overestimation of accumulation. Environ Toxicol Chem 2017;36:3223-3231. © 2017 SETAC.


Assuntos
Água Doce/análise , Sedimentos Geológicos/química , Modelos Teóricos , Poluentes Químicos da Água/análise , Conservação dos Recursos Naturais , Difusão , Praguicidas/análise , Plantas , Rios , Fatores de Tempo , Movimentos da Água
11.
Eur J Hum Genet ; 25(8): 930-934, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28612834

RESUMO

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos dos Cromossomos Sexuais/genética , Trissomia/genética , Cariótipo XYY/genética , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Trissomia/diagnóstico , Cariótipo XYY/diagnóstico
12.
Brain ; 140(6): 1579-1594, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444220

RESUMO

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value.


Assuntos
Canais de Cálcio/genética , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Canalopatias/genética , Canalopatias/fisiopatologia , Metaloendopeptidases/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genes Dominantes , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
13.
J Med Genet ; 54(6): 371-380, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289185

RESUMO

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.


Assuntos
Face/anormalidades , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Doenças Renais Policísticas/genética , Proteínas/genética , Retinite Pigmentosa
14.
Hum Mutat ; 38(5): 581-593, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28236341

RESUMO

Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.


Assuntos
Estudos de Associação Genética , Heterozigoto , Mutação , Receptor de Endotelina B/genética , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Biologia Computacional/métodos , Análise Mutacional de DNA , Exoma , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Espaço Intracelular/metabolismo , Iris , Masculino , Taxa de Mutação , Linhagem , Fenótipo , Transporte Proteico , Sítios de Splice de RNA , Receptor de Endotelina B/metabolismo , Adulto Jovem
15.
Nat Genet ; 48(8): 877-87, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399968

RESUMO

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


Assuntos
Córtex Cerebral/patologia , Haploinsuficiência/genética , Deficiência Intelectual/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação/genética , Neurogênese/fisiologia , Proteínas Repressoras/genética , Anormalidades Múltiplas , Adolescente , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Animais , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Proteínas Repressoras/metabolismo , Síndrome , Adulto Jovem
16.
Eur J Hum Genet ; 24(12): 1746-1751, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27381093

RESUMO

Spondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified - by exome sequencing - two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development.


Assuntos
Anormalidades Múltiplas/genética , Proteínas do Citoesqueleto/genética , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Mutação , Fenótipo , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Exoma , Feminino , Humanos , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/patologia , Linhagem , Escoliose/genética , Escoliose/patologia , Sinostose/patologia , Vértebras Torácicas/patologia
17.
J Hum Genet ; 61(8): 693-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27193221

RESUMO

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Éxons , Facies , Feminino , Filaminas/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA
18.
PLoS One ; 11(3): e0150555, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26974433

RESUMO

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.


Assuntos
Doenças Genéticas Inatas/genética , Mutação , Osteocondrodisplasias/genética , Proteínas/genética , Adolescente , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Inatas/diagnóstico por imagem , Doenças Genéticas Inatas/metabolismo , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/metabolismo , Fenótipo , Proteínas/metabolismo , Radiografia , Retina/metabolismo , Retina/patologia , Adulto Jovem
19.
Mol Syndromol ; 6(6): 281-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27022329

RESUMO

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.

20.
Eur J Endocrinol ; 174(5): 641-50, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26903553

RESUMO

BACKGROUND: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified. OBJECTIVE: The goal of this study was to compare growth parameters according to genotype in patients with NS. SUBJECTS AND METHODS: The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes. RESULTS: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): -1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being -2.1 ± 1.3 at 2 years, and -2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated. CONCLUSION: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.


Assuntos
Estatura , Índice de Massa Corporal , Peso Corporal , Genótipo , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Adulto , Fatores Etários , Peso ao Nascer , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Masculino , Adulto Jovem
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