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1.
Am J Hum Genet ; 105(4): 844-853, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585108

RESUMO

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

2.
Hum Mutat ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549748

RESUMO

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B.

3.
Cytogenet Genome Res ; 157(4): 189-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974434

RESUMO

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.


Assuntos
Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação , Análise de Sequência de DNA/métodos , Proteínas Wnt/genética , Consanguinidade , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Turquia
4.
Brain ; 142(4): 867-884, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30879067

RESUMO

Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.

5.
Eur J Med Genet ; : 103621, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30682496

RESUMO

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

6.
Fetal Pediatr Pathol ; 38(2): 127-137, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30600745

RESUMO

BACKGROUND: Ectopia cordis (EC) is a congenital anomaly associated with heart defects and extracardiac malformations. OBJECTIVES: We determined the various presentations of EC diagnosed in our center between 2010 and 2017. RESULTS: Seven fetuses from six pregnancies with EC were detected, five during the first trimester. Three were from multiple pregnancies, and both twins had EC in one monochorionic-monoamniotic pregnancy. Abdominal wall defects were detected in six fetuses. Kyphoscoliosis, cephalocele, clubfoot and short umbilical cord were other abnormalities. Five fetuses were terminated, one fetus died in utero, and one baby died on day two of life. Postnatal evaluation performed in all cases additionally detected cleft lips/palates in two fetuses and tetralogy of Fallot in one. CONCLUSION: Outcome is poor for these fetuses, EC can occur in a multiple pregnancy, most of the abnormalities can be identified in the first trimester and fetopsy continues to add information to the intrauterine diagnosis.

7.
Am J Med Genet A ; 176(12): 2740-2750, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30548201

RESUMO

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Orelha Externa/anormalidades , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Padrões de Herança , Fenótipo , Anormalidades do Sistema Respiratório/diagnóstico , Anormalidades do Sistema Respiratório/genética , Coluna Vertebral/anormalidades , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Facies , Feminino , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Locos de Características Quantitativas , Crânio/anormalidades , Crânio/diagnóstico por imagem , Tomografia Computadorizada Espiral , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
8.
J Med Genet ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487245

RESUMO

BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. OBJECTIVE: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. RESULTS: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. CONCLUSION: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

9.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287925

RESUMO

PURPOSE: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

10.
Mol Cytogenet ; 11: 45, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30140312

RESUMO

Background: Pallister Killian syndrome (PKS, OMIM 601803) is a rare genetic disorder with a distinct phenotype caused by tissue- limited mosaicism tetrasomy of the short arm of chromosome 12, which usually cytogenetically presents as an extra isochromosome 12p.Wide phenotypic variability in PKS has been reported, ranging from pre-to perinatal death due to multiple congenital anomalies, especially diaphragmatic hernia, and classic phenotypes including seizures, severe developmental delay, macrosomia at birth, deafness, and distinct dysmorphic features, such as coarse face, temporal alopecia, a small nose with anteverted nostrils, long philtrum, and hypo-/hyper- pigmented streaks on the skin. Results: Karyotypes obtained from cultured peripheral lymphocytes of 13 cases, who were diagnosed as PKS, were normal, while karyotypes obtained from cultured skin samples and buccal mucosa revealed the supernumerary mosaic i(12p). Mosaic karyotype was found in both fibroblast and buccal mucosa in 14 of 15 patients in our series, whereas in one stillbirth, following the clinical diagnosis of PKS, skin and buccal smear samples were taken, and all karyotypes from cultured fibroblasts revealed a supernumerary i(12p), while I-FISH study showed 60% mosaicism in mucosal cells. Conclusions: We here share the clinical, cytogenetic and molecular cytogenetic findings of 15 cases with PKS phenotype and the parental origin of seven i(12p) identified by molecular analyses. To our knowledge, this is the largest series of PKS patients with parental origin study from a single center. We believe that our study makes a significant contribution to the literature because we specifically found no differences in the phenotypes of cases with either a maternal or paternal origin of the extra element and differential imprinting appeared not to be a factor.

11.
Nature ; 561(7722): E7, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29977062

RESUMO

In this Letter, the surname of author Lena Vlaminck was misspelled 'Vlaeminck'. In addition, author Kris Vleminckx should have been associated with affiliation 16 (Center for Medical Genetics, Ghent University, Ghent, Belgium). These have been corrected online.

12.
Nature ; 557(7706): 564-569, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29769720

RESUMO

The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3. Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Extremidades/embriologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Deformidades Congênitas dos Membros/genética , Receptores Acoplados a Proteínas-G/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/metabolismo , Fenótipo , Receptores Acoplados a Proteínas-G/deficiência , Ubiquitina-Proteína Ligases/metabolismo , Xenopus/genética
13.
J Steroid Biochem Mol Biol ; 181: 88-97, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29626607

RESUMO

Congenital adrenal hyperplasia (CAH) due to 11ß-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. AIM: To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. METHODS: A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. RESULTS: The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449_1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179_1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation. CONCLUSION: This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families.

14.
J Clin Res Pediatr Endocrinol ; 10(3): 206-215, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29595516

RESUMO

Objective: 17α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed puberty. The disease is associated with bi-allelic mutations in the CYP17A1 gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment outcomes of 17OHD patients. Methods: We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. CYP17A1 gene sequence alterations were investigated in all patients. Results: The mean (±standard deviation) age of patients at presentation and follow-up time was 14.6±4.2 and 5.0±2.7 years respectively. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another novel variant occurring at an ultra rare position, leading to a missense change, are reported, both of which caused 17OHD deficiency. Steroid replacement was started. The three patients with 46,XY karyotype who were raised as females underwent gonadectomy. Osteoporosis was detected in five patients. Four patients needed antihypertensive treatment. Improvement in osteoporosis was noted with gonadal steroid replacement and supportive therapy. Conclusion: 17OHD, a rare cause of CAH, should be kept in mind in patients with pubertal delay and/or hypertension. Patients with 46,XY who are raised as females require gonadectomy. Due to late diagnosis, psychological problems, gender selection, hypertension and osteoporosis are important health problems affecting a high proportion of these patients.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/fisiopatologia , Criança , Feminino , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Turquia
15.
Am J Med Genet A ; 176(1): 187-193, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29160006

RESUMO

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.


Assuntos
Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Estudos de Associação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Ubiquitina-Proteína Ligases/genética , Biomarcadores , Criança , Análise Mutacional de DNA , Diagnóstico por Imagem , Anormalidades do Olho/terapia , Facies , Feminino , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/terapia , Deformidades Congênitas dos Membros/terapia , Microcefalia/terapia , Análise de Sequência de DNA
16.
Am J Med Genet A ; 173(12): 3136-3142, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29136349

RESUMO

Frontonasal dysplasias are rare congenital malformations of frontonasal process-derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/diagnóstico , Atresia das Cóanas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Encefalocele/diagnóstico , Face/anormalidades , Cardiopatias Congênitas/diagnóstico , Agenesia do Corpo Caloso/genética , Atresia das Cóanas/genética , Estudos de Coortes , Anormalidades Craniofaciais/classificação , Anormalidades Craniofaciais/genética , Encefalocele/genética , Encefalocele/patologia , Ossos Faciais/anormalidades , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Masculino , Nariz/anormalidades , Fenótipo , Sequenciamento Completo do Exoma
17.
Am J Hum Genet ; 101(3): 391-403, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886341

RESUMO

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.


Assuntos
Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/fisiologia , Deficiências do Desenvolvimento/genética , Transtornos do Crescimento/genética , Mutação , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Animais , Ciclo Celular , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Cílios/metabolismo , Cílios/patologia , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Transtornos do Crescimento/patologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Linhagem , Fosforilação , Transdução de Sinais , Coluna Vertebral/metabolismo
18.
PLoS Genet ; 13(3): e1006683, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346496

RESUMO

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


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Predisposição Genética para Doença/genética , Deformidades Congênitas da Mão/genética , Neoplasias Hematológicas/genética , Deficiência Intelectual/genética , Mutação , Unhas Malformadas/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Células HEK293 , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/metabolismo , Unhas Malformadas/patologia , Proteínas Nucleares/metabolismo , Fenótipo
19.
J Med Genet ; 54(6): 399-403, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28280135

RESUMO

BACKGROUND: Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology. METHODS: Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function. RESULTS: In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD (NUP107). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells. CONCLUSION: Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.


Assuntos
Hérnia Hiatal/genética , Microcefalia/genética , Mutação/genética , Nefrose/genética , Síndrome Nefrótica/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Esteroides/metabolismo , Adolescente , Criança , Deficiências do Desenvolvimento/genética , Feminino , Homozigoto , Humanos , Lactente , Rim/metabolismo , Masculino , Linhagem , Fenótipo , Proteínas/genética , Turquia
20.
Nat Genet ; 49(3): 457-464, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28092684

RESUMO

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.


Assuntos
Doenças Cerebelares/genética , Exonucleases/genética , Mutação/genética , Proteínas Nucleares/genética , RNA Nuclear Pequeno/genética , Alelos , Animais , Feminino , Humanos , Masculino , Camundongos , Doenças Neurodegenerativas/genética , RNA Mensageiro/genética , Spliceossomos/genética , Peixe-Zebra
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