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1.
J Clin Invest ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513549

RESUMO

Myocardin (MYOCD) is the founding member of a class of transcriptional co-activators that bind serum response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies and, to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by co-segregation of MYOCD variants with the phenotype in four unrelated families, by in vitro transactivation studies where pathogenic variants resulted in abrogated SM gene expression, and finding megabladder in two distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.

2.
Phys Rev E ; 100(1-1): 012302, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31499859

RESUMO

Newman et al. [Phys. Rev. E 86, 026103 (2012)10.1103/PhysRevE.86.026103] showed that points uniformly distributed as independent and identically distributed random variables with nearest-neighbor interactions form clusters with a mean number of three points in each. Here, we extend our analysis to higher dimensions, ultimately going to infinite dimensions, and we show that the mean number of points per cluster rises monotonically with a limiting value of four.

3.
Clin Genet ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31441039

RESUMO

CHRM3 codes for the M3 muscarinic acetylcholine receptor that is located on the surface of smooth muscle cells of the detrusor, the muscle that effects urinary voiding. Previously, we reported brothers in a family affected by a congenital prune belly-like syndrome with mydriasis due to homozygous CHRM3 frameshift variants. In this study, we describe two sisters with bladders that failed to empty completely and pupils that failed to constrict fully in response to light, who are homozygous for the missense CHRM3 variant c.352G > A; p.(Gly118Arg). Samples were not available for genotyping from their brother, who had a history of multiple urinary tract infections and underwent surgical bladder draining in the first year of life. He died at the age of 6 years. This is the first independent report of biallelic variants in CHRM3 in a family with a rare serious bladder disorder associated with mydriasis and provides important evidence of this association.

4.
Hum Mol Genet ; 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31304552

RESUMO

The craniofacial disorder Mandibulofacial Dysostosis Guion-Almedia type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how reduced expression of this core pre-mRNA splicing factor leads to craniofacial defects. Here we use a CRISPR-Cas9 nickase strategy to generate a human EFTUD2-knockdown cell line, and show that reduced expression of EFTUD2 leads to diminished proliferative ability of these cells, increased sensitivity to endoplasmic reticulum (ER) stress and the mis-expression of several genes involved in the ER stress response. RNA-Seq analysis of the EFTUD2-knockdown cell line revealed transcriptome-wide changes in gene expression, with an enrichment for genes associated with processes involved in craniofacial development. Additionally, our RNA-Seq data identified widespread mis-splicing in EFTUD2-knockdown cells. Analysis of the functional and physical characteristics of mis-spliced pre-mRNAs highlighted conserved properties, including length and splice site strengths, of retained introns and skipped exons in our disease model. We also identified enriched processes associated with the affected genes, including cell death, cell and organ morphology and embryonic development. Together, these data support a model in which EFTUD2 haploinsufficiency leads to the mis-splicing of a distinct subset of pre-mRNAs with a widespread effect on gene expression, including altering the expression of ER stress response genes and genes involved in the development of the craniofacial region. The increased burden of unfolded proteins in the ER resulting from mis-splicing would exceed the capacity of the defective ER stress response, inducing apoptosis in cranial neural crest cells that would result in craniofacial abnormalities during development.

5.
Int J Cancer ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31251818

RESUMO

Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case-control study was designed (1,668 controls, 405 cases) in women aged 47-73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer-Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ-OR) of SNP143 was estimated unadjusted and adjusted for Tyrer-Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86-1.34) and accuracy was retained after adjustment for Tyrer-Cuzick risk and mammographic density (IQ-OR unadjusted 2.12, 95% CI% 1.75-2.42; adjusted 2.06, 95% CI 1.75-2.42). SNP143 was a risk factor for ER+ and ER- breast cancer (adjusted IQ-OR, ER+ 2.11, 95% CI 1.78-2.51; ER- 1.81, 95% CI 1.16-2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER-positive and ER-negative disease.

6.
Am J Hum Genet ; 104(5): 994-1006, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31051115

RESUMO

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.

7.
Pharmacoeconomics ; 37(8): 1011-1027, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31087278

RESUMO

BACKGROUND AND OBJECTIVE: Precision (stratified or personalised) medicine is underpinned by the premise that it is feasible to identify known heterogeneity using a specific test or algorithm in patient populations and to use this information to guide patient care to improve health and well-being. This study aimed to understand if, and how, previous economic evaluations of precision medicine had taken account of the impact of capacity constraints. METHODS: A meta-review was conducted of published systematic reviews of economic evaluations of precision medicine (test-treat interventions) and individual studies included in these reviews. Due to the volume of studies identified, a sample of papers published from 2007 to 2015 was collated. A narrative analysis identified whether potential capacity constraints were discussed qualitatively in the studies and, if relevant, which quantitative methods were used to account for capacity constraints. RESULTS: A total of 45 systematic reviews of economic evaluations of precision medicine were identified, from which 222 studies focusing on test-treat interventions, published between 2007 and 2015, were extracted. Of these studies, 33 (15%) qualitatively discussed the potential impact of capacity constraints, including budget constraints; quality of tests and the testing process; ease of use of tests in clinical practice; and decision uncertainty. Quantitative methods (nine studies) to account for capacity constraints included static methods such as capturing inefficiencies in trials or models and sensitivity analysis around model parameters; and dynamic methods, which allow the impact of capacity constraints on cost effectiveness to change over time. CONCLUSIONS: Understanding the cost effectiveness of precision medicine is necessary, but not sufficient, evidence for its successful implementation. There are currently few examples of evaluations that have quantified the impact of capacity constraints, which suggests an area of focus for future research.

8.
Science ; 364(6442)2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31123110

RESUMO

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.

9.
Breast Cancer Res Treat ; 176(1): 141-148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30941651

RESUMO

PURPOSE: To improve breast cancer risk stratification to enable more targeted early detection/prevention strategies that will better balance risks and benefits of population screening programmes. METHODS: 9362 of 57,902 women in the Predicting-Risk-Of-Cancer-At-Screening (PROCAS) study who were unaffected by breast cancer at study entry and provided DNA for a polygenic risk score (PRS). The PRS was analysed alongside mammographic density (density-residual-DR) and standard risk factors (Tyrer-Cuzick-model) to assess future risk of breast cancer based on tumour stage receptor expression and pathology. RESULTS: 195 prospective incident breast cancers had a prediction based on TC/DR/PRS which was informative for subsequent breast cancer overall [IQ-OR 2.25 (95% CI 1.89-2.68)] with excellent calibration-(0.99). The model performed particularly well in predicting higher stage stage 2+ IQ-OR 2.69 (95% CI 2.02-3.60) and ER + BCs (IQ-OR 2.36 (95% CI 1.93-2.89)). DR was most predictive for HER2+ and stage 2+ cancers but did not discriminate as well between poor and extremely good prognosis BC as either Tyrer-Cuzick or PRS. In contrast, PRS gave the highest OR for incident stage 2+ cancers, [IQR-OR 1.79 (95% CI 1.30-2.46)]. CONCLUSIONS: A combined approach using Tyrer-Cuzick/DR/PRS provides accurate risk stratification, particularly for poor prognosis cancers. This provides support for reducing the screening interval in high-risk women and increasing the screening interval in low-risk women defined by this model.

10.
Kidney Int ; 95(5): 1138-1152, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885509

RESUMO

Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.

11.
Am J Med Genet A ; 179(3): 404-409, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628148

RESUMO

The bladder exstrophy-epispadias complex (BEEC) comprises of a spectrum of anterior midline defects, all affecting the lower urinary tract, the external genitalia, and the bony pelvis. In extreme cases, the gastrointestinal tract is also affected. The pathogenesis of BEEC is unclear but chromosomal aberrations have been reported. In particular, duplications of 22q11.2 have been identified in eight unrelated individuals with BEEC. The current study aimed to identify chromosomal copy number variants in BEEC. Analyses was performed using the Affymetrix Genome-wide SNP6.0 assay in 92 unrelated patients cared for by two UK pediatric urology centers. Three individuals had a 22q11.2 duplication, a significantly higher number than that found in a control group of 12,500 individuals with developmental delay who had undergone microarray testing (p < .0001). Sequencing of CRKL, implicated in renal tract malformations in DiGeorge syndrome critical region at 22q11, in 89 individuals with BEEC lacking 22q11 duplications revealed no pathogenic variants. To date, 22q11.2 duplication is the genetic variant most commonly associated with BEEC. This is consistent with the hypothesis that altered expression of a single, yet to be defined, gene therein is critical to the pathogenesis of this potentially devastating congenital disorder.

12.
Circ Res ; 124(4): 553-563, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30582441

RESUMO

RATIONALE: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. OBJECTIVE: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. METHODS AND RESULTS: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. CONCLUSIONS: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

13.
J Nerv Ment Dis ; 207(1): 43-44, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30575708

RESUMO

Recently, ketamine has seen increased use among emergency medical services in the prehospital setting as a first-line means of chemical restraint for agitated patients. In this case report, we explore an instance in which ketamine administration for nonpsychotic agitation before emergency department (ED) evaluation may have caused unexpected psychotic symptoms leading to a complicated ED course necessitating admission. As ketamine gains widespread use in the prehospital setting, the safety profile deserves reevaluation. In the following report, we review relevant literature and discuss important factors to consider regarding the use of prehospital ketamine, including psychiatric and substance abuse history.

14.
J Am Acad Psychiatry Law ; 46(4): 521-531, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30593482

RESUMO

In June 2017, a media frenzy ensued after Michelle Carter was convicted of involuntary manslaughter in the state of Massachusetts for facilitating the suicide of Conrad Roy. The verdict stirred controversy and cast a spotlight on facilitation of suicide, i.e., a person's act(s) done with the purpose of helping another to die by suicide. One form of facilitation, physician-assisted suicide, has been extensively debated in the existing literature. In this article, we set out to explore the legal and forensic ramifications of non-physician-assisted suicide, which we refer to as facilitated suicide. We first conducted a review of all fifty states' legislation regarding facilitated suicide: forty-four states prohibit it by statute, and three states prohibit it through common law. Thirteen states specifically outlaw verbal facilitation of suicide. We then surveyed the case law to identify legal precedent to the Commonwealth v. Carter verdict. Final Exit Network, Inc. v. State and State v. Melchert-Dinkel provide contrasting yet complementary perspectives on the interplay between speech and assisted suicide. Finally, we detailed the role of forensic psychiatry in investigating facilitated suicide, specifically among adolescents and youths.


Assuntos
Suicídio Assistido/legislação & jurisprudência , Feminino , Humanos , Masculino , Estados Unidos
15.
J Hum Genet ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459467

RESUMO

Determining the clinical significance of germline and somatic KMT2D missense variants (MVs) in Kabuki syndrome (KS) and cancers can be challenging. We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in individuals with KS (KS-MVs). The proportion of MVs likely to affect splicing was significantly higher for Cancer-MVs and KS-MVs than in Control-MVs (p = 0.000018). Our analysis identified significant clustering of Cancer-MVs and KS-MVs in the PHD#3 and #4, RING#4 and SET domains. Areas of enrichment restricted to just Cancer-MVs (FYR-C and between amino acids 3043-3248) or KS-MVs (coiled-coil#5, FYR-N and between amino acids 4995-5090) were also found. Cancer-MVs and KS-MVs tended to affect more conserved residues (lower BLOSUM scores, p < 0.001 and p = 0.007). KS-MVs are more likely to increase the energy for protein folding (higher ELASPIC ∆∆G scores, p = 0.03). Cancer-MVs are more likely to disrupt protein interactions (higher StructMAn scores, p = 0.019). We reclassify several presumed pathogenic MVs as benign or as variants of uncertain significance. We raise the possibility of as yet unrecognised 'non-KS' phenotype(s) associated with some germline pathogenic KMT2D MVs. Overall, this work provides insights into the disease mechanism of KMT2D variants and can be extended to other genes, mutations in which also cause developmental syndromes and cancer.

17.
Eur J Med Genet ; 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217753

RESUMO

Melkersson Rosenthal syndromes (MRS) is a rare autosomal dominantly inherited neurocutaneous syndrome characterised by a triad of facial (seventh cranial) nerve palsy, recurrent orofacial swelling and fissuring of the tongue. A recent report implicated a heterozygous missense variant in SLC27A1 (FATP1) as the cause of this condition in members of an affected Chinese family. We undertook Sanger sequencing of this gene in 14 affected unrelated individuals affected by MRS. We did not detect any putative pathogenic variants. Our data indicates that there is both clinical and genetic heterogeneity in this condition and that the causative gene remains to be identified for the majority of cases.

18.
J Neurosurg ; : 1-7, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30117767

RESUMO

OBJECTIVE Neurosurgery is often self-selecting. Concern has been raised that residents in the millennial era (born between 1982 and 2004) may have more serious professionalism and performance issues (PPIs) during training compared to prior trainees. Serious PPIs were defined as concerns that led to specific resident disciplinary actions ranging from initial warnings to termination. In order to evaluate this concern, the authors retrospectively reviewed a 50-year experience at a single training center. They then prospectively surveyed living graduates of the program to assess variations in practice patterns and job satisfaction over 5 decades. METHODS The PPIs of 141 residents admitted for training at the University of Pittsburgh (subsequently UPMC) Department of Neurological Surgery were reviewed by decade starting in 1971 when the first department chair was appointed. The review was conducted by the senior author, who served from 1975 to 1980 as a resident, as a faculty member since 1980, and as the resident director since 1986. A review of resident PPIs between 1971 and 1974 was performed in consultation with a senior faculty member active at that time. During the last decade, electronic reporting of PPIs was performed by entry into an electronic reporting system. In order to further evaluate whether the frequency of PPIs affected subsequent job satisfaction and practice patterns after completion of training, the authors surveyed living graduates. RESULTS There was no statistically significant difference by decade in serious PPIs. Although millennial residents had no significant increase in the reporting of serious PPIs, the increased use of electronic event reporting over the most recent 2 decades coincided with a trend of increased reporting of all levels of suspected PPIs (p < 0.05). Residents surveyed after completion of training showed no difference by decade in types of practice or satisfaction-based metrics (p > 0.05) but reported increasing concerns related to the impact of their profession on their own lifestyle as well as their family's. CONCLUSIONS There was no statistically significant difference in the incidence of serious PPIs over 5 decades of training neurosurgery residents at the authors' institution. During the millennial era, serious PPIs have not been increasing. However, reporting of all levels of PPIs is increasing coincident with the ease of electronic reporting. There was remarkably little variance in satisfaction metrics or type of practice over the 5 decades studied.

19.
Am J Hum Genet ; 103(2): 213-220, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30075112

RESUMO

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.-107A>T in the BRCA1 5' UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5' UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.

20.
Hum Genet ; 2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29974297

RESUMO

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

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