Case report : A novel de novo IGF2 missense variant in a Finnish patient with Silver-Russell syndrome

Silver-Russell syndrome (SRS, OMIM 180860) is a rare imprinting disorder characterized by intrauterine and postnatal growth restriction, feeding difficulties in early childhood, characteristic facial features, and body asymmetry. The molecular cause most commonly relates to hypomethylation of the imprinted 11p15.5 IGF2/H19 domain but remains unknown in about 40% of the patients. Recently, heterozygous paternally inherited pathogenic variants in IGF2, the gene encoding insulin-like growth factor 2 (IGF2), have been identified in patients with SRS. We report a novel de novo missense variant in IGF2 (c.122T > G, p.Leu41Arg) on the paternally derived allele in a 16-year-old boy with a clinical diagnosis of SRS. The missense variant was identified by targeted exome sequencing and predicted pathogenic by multiple in silico tools. It affects a highly conserved residue on a domain that is important for binding of other molecules. Our finding expands the spectrum of disease-causing variants in IGF2. Targeted exome sequencing is a useful diagnostic tool in patients with negative results of common diagnostic tests for SRS.Peer reviewe

Mosaic Deletions of Known Genes Explain Skeletal Dysplasias With High and Low Bone Mass

Mosaicism, a state in which an individual has two or more genetically distinct populations of cells in the body, can be difficult to detect because of either mild or atypical clinical presentation and limitations in the commonly used detection methods. Knowledge of the role of mosaicism is limited in many skeletal disorders, including osteopathia striata with cranial sclerosis (OSCS) and cleidocranial dysplasia (CCD). We used whole-genome sequencing (WGS) with coverage >40x to identify the genetic causes of disease in two clinically diagnosed patients. In a female patient with OSCS, we identified a mosaic 7-nucleotide frameshift deletion in exon 2 of AMER1, NM_152424.4:c.855_861del:p.(His285Glnfs*7), affecting 8.3% of the WGS reads. In a male patient with CCD, approximately 34% of the WGS reads harbored a 3710-basepair mosaic deletion, NC_000006.11:g.45514471_45518181del, starting in intron 8 of RUNX2 and terminating in the 3 ' untranslated region. Droplet digital polymerase chain reaction was used to validate these deletions and quantify the absolute level of mosaicism in each patient. Although constitutional variants in AMER1 and RUNX2 are a known cause of OSCS and CCD, respectively, the mosaic changes here reported have not been described previously. Our study indicates that mosaicism should be considered in unsolved cases of skeletal dysplasia and should be investigated with comprehensive and sensitive detection methods. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Peer reviewe

Four novel mutations in the OFD1 (Cxorf5) gene in Finnish patients with oral-facial-digital syndrome 1

Peer reviewe

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH result (vol 13, 84, 2012)

Peer reviewe

Universality in two-dimensional Kardar-Parisi-Zhang growth

We analyze simulations results of a model proposed for etching of a crystalline solid and results of other discrete models in the 2+1-dimensional Kardar-Parisi-Zhang (KPZ) class. In the steady states, the moments W_n of orders n=2,3,4 of the heights distribution are estimated. Results for the etching model, the ballistic deposition (BD) model and the temperature-dependent body-centered restricted solid-on-solid model (BCSOS) suggest the universality of the absolute value of the skewness S = W_3 / (W_2)^(3/2) and of the value of the kurtosis Q = W_4 / (W_2)^2 - 3. The sign of the skewness is the same of the parameter \lambda of the KPZ equation which represents the process in the continuum limit. The best numerical estimates, obtained from the etching model, are |S| = 0.26 +- 0.01 and Q = 0.134 +- 0.015. For this model, the roughness exponent \alpha = 0.383 +- 0.008 is obtained, accounting for a constant correction term (intrinsic width) in the scaling of the squared interface width. This value is slightly below previous estimates of extensive simulations and rules out the proposal of the exact value \alpha=2/5. The conclusion is supported by results for the ballistic deposition model. Independent estimates of the dynamical exponent and of the growth exponent are 1.605 <= z <= 1.64 and \beta = 0.229 +- 0.005, respectively, which are consistent with the relations \alpha + z = 2 and z = \alpha / \beta.Comment: 8 pages, 9 figures, to be published in Phys. Rev.

Incidência e prevalência da disfunção erétil e ejaculatória em estudantes de medicina nas cidades de Goiania e Anápolis

RESUMO: A disfunção sexual é um distúrbio que tem por característica se pronunciar com o avançar da idade e dos fatores sociais e pessoais que envolve o indivíduo. Dentre as principais disfunções sexuais encontra-se a disfunção erétil e a ejaculação precoce como as mais prevalentes, sendo estas determinadas por vários fatores predisponentes de tais patologias, como fatores orgânicos e psicológicos. Nesse sentido, espera-se quemesmo os estudantes de medicina, que normalmente representam uma população jovem e saudável, devido a fatores como o estresse físico, emocional e mental, proporcionadas por sua rotina, podem acabar tendo sua sexualidade afetada, tornando-se possíveis vítimas da disfunção sexual. Esses transtornos sexuais podem então somatizar negativamente na vida de um estudante universitário de medicina, prejudicando suaqualidade de vida e até ser um fator predisponente para doenças psicossociais. Dessa forma, o presente estudo tem por objetivo identificar a incidência e a prevalência da disfunção erétil e ejaculatória em estudantes de medicina de escolas médicas da cidade de Goiânia e de Anápolis, relacionando fatores predisponentes e de rotina dessa população. Trata-se de um estudo primário, observacional, de prevalência, transversal, descritivo e quantitativo. Como instrumento de coleta de dados serão aplicados questionários aos participantes com base em dados da Associação Americana de Urologia (AUA), os quais serão realizados em escolas de medicina das cidades de Goiânia e Anápolis. Espera-se encontrar uma estimativa sobre a incidência e a prevalência de disfunção erétil e ejaculatória masculina nos acadêmicos de medicina. Acredita-se que esses estudantes não tenham o conhecimento adequado sobre os fatores predisponentes e consequências da disfunção sexual e como isso pode refletir na sua vida acadêmica

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results

Erratum to: high-resolution SNP array analysis of patients with developmental disorder and normal array CGH result BMC Medical Genetics 2014, 15:124 10.1186/s12881-014-0124-3Peer reviewe

Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal disorders : evidence from SNP arrays

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD.Peer reviewe

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD