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1.
Nat Commun ; 11(1): 4287, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855419

RESUMO

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.


Assuntos
Anormalidades Múltiplas/etiologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Quadruplex G , Troca de Cromátide Irmã , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proliferação de Células , RNA Helicases DEAD-box/química , DNA Helicases/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estabilidade Proteica , Pseudogenes , RNA Helicases/genética , RNA Helicases/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Síndrome , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
2.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
3.
Tunis Med ; 98(5): 420-422, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548846

RESUMO

Cystic Fibrosis (CF) is a lethal autosomal recessive condition due to a defect at the level of the transmembrane conductance regulator gene which plays a role in cell homeostasis. Numerous mutations have been identified as the cause of this gene defect, with delF508 being one of the most common mutations in Tunisia. This is a case report describing, up to our knowledge, the second case of a patient with CF carrying a rare mutation: W19X. W19X is a nonsense mutation that has been previously identified in only one other Tunisian patient with CF. Since both incidence of this mutation have been described in Tunisia, it seems as if W19X is specific to Tunisian CF patient with significant morbidities. The information provided by this study contributes to defining the molecular spectrum of CF in Tunisia, in the aim of improving genetic testing and prenatal diagnosis.


Assuntos
Códon sem Sentido , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Fibrose Cística/diagnóstico , Fibrose Cística/patologia , Frequência do Gene , Testes Genéticos , Humanos , Triptofano/genética , Tunísia
4.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
5.
Urologe A ; 59(7): 825-828, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32472223

RESUMO

Aphallia is an extremely rare congenital malformation of unknown cause. The incidence is reported in the literature to be 1 in 10-30 million live births. Almost 100 cases have been described to date. Aphallia is associated with other congenital malformations (in particular urogenital and gastrointestinal anomalies) in >50% of cases. The diagnosis is made clinically and shows the complete absence of the corpora cavernosa and the corpus spongiosum with a urethral opening along the perineal midline (most frequently ventral to the anus and in the ventral rectal wall). Two case reports from the authors' department: The first child was a male newborn (46,XY) with penis agenesis and additional bilateral intraabdominal testis, an anorectal malformation (ARM) with a rectovesical fistula, as well as left renal duplication and grade III vesico-ureteral reflux on the right side. The second child was a male newborn (46,XY) with aphallia without further urological or anorectal malformation. Only right inguinal hernia was present. In the first patient, several corrective surgeries were performed in the further course in view of the additional malformations. With regard to the aphallia, the various temporary treatment options (scrotal or parascrotal phalloplasty or penis prosthesis) were discussed with the parents. Masculinizing surgery by means of definitive phalloplasty was planned once the patient has reached puberty. Due to the technical demands of phallus reconstruction, feminization is still favored in some countries in the literature, which nowadays, however, cannot be justified medically or legally.


Assuntos
Anormalidades Múltiplas/patologia , Malformações Anorretais , Doenças dos Genitais Masculinos , Rim/anormalidades , Pênis/anormalidades , Anormalidades Urogenitais/patologia , Androgênios , Criança , Humanos , Recém-Nascido , Masculino , Escroto , Maturidade Sexual , Uretra
6.
Cytogenet Genome Res ; 160(4): 185-192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32316019

RESUMO

A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Contactinas/genética , Feminino , Humanos , Fenótipo , Receptores de AMPA/genética , Fatores de Transcrição/genética
7.
Clin Sci (Lond) ; 134(8): 941-953, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227118

RESUMO

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Diarreia/congênito , Células Epiteliais/metabolismo , Erros Inatos do Metabolismo/genética , Trocador 3 de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/mortalidade , Diarreia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Knockout , Mutação , Trocador 3 de Sódio-Hidrogênio/metabolismo
8.
BMC Med Genet ; 21(1): 80, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295525

RESUMO

BACKGROUND: Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive. CASE PRESENTATION: We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems. CONCLUSIONS: This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.


Assuntos
Anormalidades Múltiplas/genética , Laminina/genética , Síndromes Miastênicas Congênitas/genética , Síndrome Nefrótica/genética , Distúrbios Pupilares/genética , Anormalidades Múltiplas/patologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Lactente , Masculino , Mutação , Síndromes Miastênicas Congênitas/patologia , Síndrome Nefrótica/patologia , Fenótipo , Distúrbios Pupilares/patologia
9.
World Neurosurg ; 138: 461-467, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32200015

RESUMO

Caudal regression syndrome (CRS) represents a spectrum of clinical phenotypes with varying degrees of malformation of the lower body with involvement of structures deriving from all 3 layers of the trilaminar embryo. We review areas of active investigation in the diagnosis, etiology, epidemiology, and treatment of the disease with a focus on underlying genetics. CRS pathobiology is complex and multifactorial with a significant contribution from environmental factors as evidenced in twin studies. Contemporary genomic and genetic investigations in both human primary tissue and murine in vitro and in vivo models implicate various genes associated with caudal differentiation and neural cell migration in embryogenesis. A large number of identified targets center around the metabolic regulation of retinoic acid and its derivatives. Dysregulation of retinoic acid homeostasis has been associated with abnormal embryonic cell migration, differentiation, and organogenesis with resulting malformations and agenesis in both a laboratory and a clinical setting. There appears to be a significant overlap in potential genetic targets with CRS and other developmental syndromes with similar presentations, such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. CRS represents a spectrum of caudal developmental abnormalities with treatment options limited to mild and moderate expressions of disease. Continued research is necessary to further clarify mechanisms of disease pathobiology and complex polygenetic and environmental interaction. Despite this, progress has been made in identifying genetic targets and downstream effectors contributing to preclinical and clinical progression.


Assuntos
Anormalidades Múltiplas/genética , Genômica , Deformidades Congênitas dos Membros/genética , Malformações do Sistema Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Animais , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/patologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Tretinoína/metabolismo
10.
Hum Genet ; 139(2): 257-271, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31942643

RESUMO

Severe asthenozoospermia is a common cause of male infertility. Recent studies have revealed that SPEF2 mutations lead to multiple morphological abnormalities of the sperm flagella (MMAF) without primary ciliary dyskinesia (PCD) symptoms in males, but PCD phenotype was also found in one female individual. Therefore, whether there is a phenotypic continuum ranging from infertile patients with PCD to MMAF patients with no or low noise PCD manifestations remains elusive. Here, we performed whole-exome sequencing in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. We identified four novel biallelic mutations in SPEF2 (8.9%, 4/45) in six affected individuals (12.8%, 6/47), while no deleterious biallelic variants in SPEF2 were detected in 637 controls, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia, and 223 fertile controls. Notably, all six patients exhibited PCD-like symptoms, including recurrent airway infections, bronchitis, and rhinosinusitis. Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory cilia but consistently abnormal 9 + 0 axoneme or disordered accessory structures of sperm flagella, indicating different roles of SPEF2 in sperm flagella and respiratory cilia. Subsequently, a Spef2 knockout mouse model was used to validate the PCD-like phenotype and male infertility, where the subfertility of female Spef2-/- mice was found unexpectedly. Overall, our data bridge the link between MMAF and PCD based on the association of SPEF2 mutations with both infertility and PCD in males and provide basis for further exploring the molecular mechanism of SPEF2 during spermiogenesis and ciliogenesis.


Assuntos
Anormalidades Múltiplas/patologia , Proteínas de Ciclo Celular/genética , Cílios/patologia , Transtornos da Motilidade Ciliar/patologia , Infertilidade Masculina/patologia , Proteínas/fisiologia , Cauda do Espermatozoide/patologia , Anormalidades Múltiplas/genética , Animais , Cílios/genética , Transtornos da Motilidade Ciliar/genética , Feminino , Humanos , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Motilidade Espermática , Cauda do Espermatozoide/metabolismo
11.
Nat Med ; 26(1): 98-109, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932796

RESUMO

Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.


Assuntos
Anormalidades Múltiplas/patologia , Bancos de Espécimes Biológicos , Fatores de Troca do Nucleotídeo Guanina/genética , Fenômica , Proteínas de Peixe-Zebra/genética , Animais , Comportamento Animal , Condrócitos/patologia , Condrócitos/ultraestrutura , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Humanos , Modelos Biológicos , Sistema Musculoesquelético/patologia , Osteogênese , Fenótipo , Pró-Colágeno/metabolismo , Transporte Proteico , Via Secretória , Síndrome , Peixe-Zebra
12.
Clin Dysmorphol ; 29(1): 24-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30946036

RESUMO

Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cistos , Família , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Lábio/anormalidades , Linhagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Cistos/genética , Cistos/patologia , República Democrática do Congo , Feminino , Humanos , Lábio/patologia , Masculino
13.
Clin Dysmorphol ; 29(1): 46-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31205051
14.
Clin Dysmorphol ; 29(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31577543

RESUMO

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.


Assuntos
Anormalidades Múltiplas , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Masculino , Retina/patologia , Retina/fisiopatologia
15.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544945

RESUMO

OBJECTIVE: IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations. RESULTS: We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.-6-1G>C) leading to skipping of exon 2 and cases 2-5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver-Russell syndrome (SRS) phenotype with Netchine-Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1-4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values. CONCLUSIONS: This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Metilação de DNA , Impressão Genômica , Fator de Crescimento Insulin-Like II/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Masculino , Herança Paterna , Prognóstico , RNA Longo não Codificante/genética , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patologia , Adulto Jovem
16.
Am J Hum Genet ; 106(1): 121-128, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883643

RESUMO

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.


Assuntos
Anormalidades Múltiplas/patologia , Transtornos do Desenvolvimento Sexual/patologia , Holoprosencefalia/patologia , Mutação , Fosfatase de Miosina-de-Cadeia-Leve/genética , Anormalidades Urogenitais/patologia , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/genética , Feminino , Idade Gestacional , Holoprosencefalia/genética , Humanos , Masculino , Fenótipo , Gravidez , Anormalidades Urogenitais/genética
17.
Am J Hum Genet ; 105(6): 1294-1301, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31761294

RESUMO

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.


Assuntos
Anormalidades Múltiplas/etiologia , Doenças do Desenvolvimento Ósseo/etiologia , Ectromelia/etiologia , Quadril/anormalidades , Homozigoto , Ísquio/anormalidades , Mutação com Perda de Função , Pneumopatias/etiologia , Pulmão/anormalidades , Patela/anormalidades , Pelve/anormalidades , Proteínas com Domínio T/genética , Anormalidades Múltiplas/patologia , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Criança , Ectromelia/patologia , Feminino , Quadril/patologia , Humanos , Ísquio/patologia , Pulmão/patologia , Pneumopatias/patologia , Masculino , Patela/patologia , Linhagem , Pelve/patologia , Prognóstico
18.
Blood Coagul Fibrinolysis ; 30(8): 423-425, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738289

RESUMO

: Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder caused by a defective function of glycoprotein (GP) Ib-V-IX complex. Among the genes encoding the 4 receptor subunits (GPIbα, GPIbß, GPV and GPIX), the GPIbß gene is located on chromosomes 22q11.2. We report a case of a girl with BSS associated with clinical features of 22q11.2 deletion syndrome (22q11.2DS) with phenotypic spectrum of DiGeorge syndrome/velocardiofacial syndrome. She has a history of life-long bleeding tendency, tetralogy of Fallot, hypothyroidism, mild facial dysmorphic signs and macrothrombocytopenia. The BBS and 22q11.2DS association could be explained by the fact that the constitutional hemizygosity of 22q11.2 may unmask an autosomal recessive disorder caused by alterations of the nondeleted GPIbß allele. We suggest that all patients with 22q11.2DS and bleeding manifestations should be always tested for BSS.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/patologia , Anormalidades Múltiplas/patologia , Síndrome de Bernard-Soulier/patologia , Deleção Cromossômica , Síndrome de DiGeorge/genética , Feminino , Hemorragia , Humanos , Complexo Glicoproteico GPIb-IX de Plaquetas , Adulto Jovem
19.
Ethiop J Health Sci ; 29(3): 413-416, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31447511

RESUMO

Background: Lumbo-costo-vertebral syndrome is a set of rare abnormalities involving vertebral bodies, ribs, and abdominal wall. Case: We present a case of Lumbo-costo-vertebral syndrome in a 6-month old female infant who had a progressive swelling over the right lumbar area since birth. Clinical examination revealed a reducible swelling on the right flank with positive cough impulse. Ultrasonography showed a defect containing bowel loops in the right lumbar region. Chest X-ray revealed scoliosis and hemivertebrae with absent lower ribs on the right side. Computer tomography scan showed hernia sac containing the bowel and the right lobe of the liver with cross fused kidney. Conclusion: Lumbo-costo-vertebraly syndrome is a rare condtion which could be associated with different organ malformations. Simple closure or meshplasty could be done depending on the size of the defect.


Assuntos
Anormalidades Múltiplas/patologia , Hérnia Abdominal/congênito , Vértebras Lombares/anormalidades , Costelas/anormalidades , Parede Abdominal/anormalidades , Feminino , Humanos , Lactente , Escoliose/congênito , Síndrome
20.
J Pediatr Endocrinol Metab ; 32(9): 995-1003, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31369396

RESUMO

Background This study aimed to evaluate the imaging findings of patients who underwent an abdominal and pelvic magnetic resonance imaging (MRI) due to primary amenorrhea. Methods The pelvic and abdominal images of 34 female patients (mean age 15.61 years, range 14-19 years) were retrospectively analyzed by a single radiologist blinded to the clinical and laboratory data of the patients (other than primary amenorrhea) to evaluate the etiology of primary amenorrhea. The anatomy and anomalies of the internal genital organs and other accompanying abdominopelvic anomalies were investigated. Results Gonadal dysgenesis was present in 14 patients (41.17%) and Müllerian duct anomalies (MDAs) were present in 20 (58.83%) (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome in 13 [65%], distal vaginal obstruction [DVO] findings in five [25%], and obstructed hemivagina and ipsilateral renal anomaly [OHVIRA] syndrome in two [10%]). Seven patients with MRKH (53.84%) were of type 1 and six (46.15%) were of type 2. A total of eight additional anomalies (vertebral and renal) were detected, six in MRKH and two in OHVIRA syndrome cases. Endometrioma and hematosalpinx were observed in one of the five patients with DVO (5%). Conclusions Primary amenorrhea is a common symptom that affects both the physical and psychosocial status of individuals. Determination of the underlying etiology is the first step in planning treatment. The evaluation of internal genital organ anomalies involved in the etiology is important for sexual function and fertility. MRI is a non-invasive imaging modality that should be preferred in these cases as it provides detailed data about the anatomy and anomalies of internal genital organs due to its high soft tissue contrast resolution.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/complicações , Anormalidades Múltiplas/patologia , Insuficiência Adrenal/complicações , Disgenesia Gonadal/etiologia , Nefropatias/complicações , Imagem por Ressonância Magnética/métodos , Ductos Paramesonéfricos/anormalidades , Osteocondrodisplasias/complicações , Anormalidades Urogenitais/complicações , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Adolescente , Insuficiência Adrenal/patologia , Adulto , Anormalidades Congênitas/patologia , Feminino , Retardo do Crescimento Fetal/patologia , Seguimentos , Disgenesia Gonadal/patologia , Humanos , Nefropatias/patologia , Ductos Paramesonéfricos/patologia , Osteocondrodisplasias/patologia , Prognóstico , Estudos Retrospectivos , Anormalidades Urogenitais/patologia , Adulto Jovem
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