Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Associated With a Novel Mutation of FOXP3 Gene

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, x-linked, recessive disorder characterized by dysfunction of the T regulatory (Treg) lymphocytes leading to autoimmune diseases. Herein we report a male patient with IPEX syndrome who presented with severe diarrhea, eczema, and malabsorption leading to failure to thrive and necessitating total parenteral nutrition, as well as with liver dysfunction. Laboratory investigation showed elevated liver enzymes that declined following treatment with glucocorticosteroids and immunosuppressive drugs, marked eosinophilia, increased total IgE, and decreased Treg cells. DNA analysis revealed that the patient himself was hemizygous and his mother heterozygous for the exon 10, c.1015C>T (p.Pro339Ser) mutation of the FOXP3 gene, which has not been previously reported. The current case indicates that mutations resulting in substitution of a certain amino-acid (i.e., proline 339) by different amino-acids are manifested with different IPEX phenotypes

A novel Desmoplakin mutation associated with left dominant arrhythmogenic cardiomyopathy and cutaneous phenotype

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Prenatal diagnosis of Wolf-Hirschhorn syndrome confirmed by comparative genomic hybridization array: report of two cases and review of the literature

Wolf-Hirschhorn syndrome (WHS) is a well known genetic condition caused by a partial deletion of the short arm of chromosome 4. The great variability in the extent of the 4p deletion and the possible contribution of additional genetic rearrangements lead to a wide spectrum of clinical manifestations. The majority of the reports of prenatally diagnosed WHS cases are associated with large 4p deletions identified by conventional chromosome analysis; however, the widespread clinical use of novel molecular techniques such as array comparative genomic hybridization (a-CGH) has increased the detection rate of submicroscopic chromosomal aberrations associated with WHS phenotype. We provide a report of two fetuses with WHS presenting with intrauterine growth restriction as an isolated finding or combined with oligohydramnios and abnormal Doppler waveform in umbilical artery and uterine arteries. Standard karyotyping demonstrated a deletion on chromosome 4 in both cases [del(4)(p15.33) and del(4)(p15.31), respectively] and further application of a-CGH confirmed the diagnosis and offered a precise characterization of the genetic defect. A detailed review of the currently available literature on the prenatal diagnostic approach of WHS in terms of fetal sonographic assessment and molecular cytogenetic investigation is also provided

Detailed molecular and clinical investigation of a child with a partial deletion of chromosome 11 (Jacobsen syndrome)

<p>Abstract</p> <p>Background</p> <p>Jacobsen syndrome (JBS) is a rare chromosomal disorder leading to multiple physical and mental impairment. This syndrome is caused by a partial deletion of chromosome 11, especially subband 11q24.1 has been proven to be involved. Clinical cases may easily escape diagnosis, however pancytopenia or thrombocytopenia may be indicative for JBS.</p> <p>Results</p> <p>We report a 7.5 years old boy presenting with speech development delay, hearing impairment and abnormal platelet function. High resolution SNP oligonucleotide microarray analysis revealed a terminal deletion of 11.4 Mb in size, in the area 11q24.1-11qter. This specific deletion encompasses around 170 genes. Other molecular techniques such as fluorescence in situ hybridization and multiplex ligation-dependent probe amplification were used to confirm the array-result.</p> <p>Discussion</p> <p>Our results suggest that the identification and detailed analysis of similar patients with abnormal platelet function and otherwise mild clinical features will contribute to identification of more patients with 11q deletion and JBS.</p

Prenatal diagnosis of Baraitser-Winter syndrome using exome sequencing: Clinical report and review of literature

Baraitser - Winter Cerebrofrontofacial Syndrome (BWCFF) is a rare disorder characterized by facial dysmorphism and mental retardation of varying grades. The clinical phenotype of BWCFF indicates variable phenotypic expression involving various congenital malformations such as cardiac, renal and musculoskeletal abnormalities. Nevertheless, the prenatal presentation of BWCFF is rarely described, making prenatal diagnosis challenging. This report describes a prenatal diagnosis of BWCFF syndrome to date; a case of a fetus with intrauterine growth restriction, increased nuchal fold, bilateral hydronerphosis, rocker bottom foot and clubfoot detected on Anomaly Scan is outlined. Molecular karyotype failed to detect any abnormality. Assessment with Next Generation Sequencing was then performed, revealing a heterozygous de novo mutation in ACTB gene setting the diagnosis of BWCFF

Routine use of array comparative genomic hybridization (aCGH) as standard approach for prenatal diagnosis of chromosomal abnormalities. Clinical experience of 1763 prenatal cases

Objective: This study aims to evaluate the diagnostic yield of comparative genomic hybridization microarrays (aCGH) and compare it with conventional karyotype analysis of standard >5-Mb resolution. Method: A total of 1763 prenatal samples were analyzed by aCGH (CytoChip Focus Constitutional microarrays, BlueGnome, Cambridge). The diagnostic yield of chromosomal abnormalities detected by aCGH was assessed, compared with conventional karyotype analysis. Results: The result was pathogenic/unknown penetrance in 125 cases (7.1%), and a variant of unknown significance (VOUS) was detected in 13 cases (0.7%). Out of the 125 cases with abnormal findings, 110 were also detected by conventional karyotype analysis. The aCGH increment in diagnostic yield was 0.9% (15/1763) and 1.6% when VOUS were included. Stratifying the sample according to indications for prenatal invasive testing, the highest values of diagnostic yield increment were observed for patients positive for second-trimester sonographic markers (1.5%) and for the presence of fetal structural anomalies (1.3%). In contrast, the incremental yield was marginal in patients with fetus with increased nuchal translucency (0.5%). Conclusion: The present study indicates that routine implementation of aCGH offers an incremental yield over conventional karyotype analysis, which is also present in cases with 'milder' indications, further supporting its use as a first-tier test. What's already known about this topic? Array CGH has an incremental yield over conventional cytogenetics, which has been mostly highlighted in cases of fetuses with structural defects. What does this study add? The present study is one of the few large cohort studies that support the use of aCGH as a first-tier test for prenatal diagnosis of chromosomal abnormalities, with a significant increase of the incremental diagnostic yield of chromosomal abnormalities. Apart from fetuses with structural defects, an incremental diagnostic yield was also observed for cases with milder indications for invasive testing, for example, second-trimester markers or advanced maternal age, supporting the preferable use of more comprehensive diagnostic approaches in prenatal testing of chromosomal abnormalities

Prenatal Identification of a Novel Mutation in the <i>MCPH1</i> Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS): A Case Report and Review of the Literature

Background: MCPH1 is known as the microcephalin gene (OMIM: *607117), of which the encoding protein is a basic regulator of chromosome condensation (BCRT-BRCA1 C-terminus). The microcephalin protein is made up of three BCRT domains and conserved tandem repeats of interacting phospho-peptides. There is a strong connection between mutations of the MCPH1 gene and reduced brain growth. Specifically, individuals with such mutations have underdeveloped brains, varying levels of mental retardation, delayed speech and poor language skills. Methods: In this article, a family with two affected fetuses presenting a mutation of the MCPH1 gene is reported. During the first trimester ultrasound of the second pregnancy, the measure of nuchal translucency was increased (NT = 3.1 mm) and, therefore, the risk for chromosomal abnormalities was high. Chorionic villi sampling (CVS) was then performed. Afterwards, fetal karyotyping and Next Generation Sequencing were carried out. Afterwards, NGS was also performed in a preserved sample of the first fetus which was terminated due to microcephaly. Results: In this case, the fetuses had a novel homozygous mutation of the MCPH1 gene (c.348del). Their parents were heterozygous for the mutation. The fetuses showed severe microcephaly. Because of the splice sites in introns, this mutation causes the forming of dysfunctional proteins which lack crucial domains of the C-terminus. Conclusion: Our findings portray an association between the new MCPH1 mutation (c.348del) and the clinical features of autosomal recessive primary microcephaly (MCPH), contributing to a broader spectrum related to these pathologies. To our knowledge, this is the first prenatal diagnosis of MCPH due to a novel MCPH1 mutation

Autism spectrum disorder, anxiety and severe depression in a male patient with deletion and duplication in the 21q22.3 region: A case report

In this report, a patient carrying a 650 kb deletion and a 759 kb duplication of chromosomal 21q22.3 region was described. Facial dysmorphic features, hypotonia, short stature, learning impairment, autism spectrum disorder, anxiety and depression were observed clinical characteristics. Mentioned copy number variants were the shortest in length reported so far. The current study hypothesized that the presence of a susceptibility locus for autism spectrum disorder associated with depression and anxiety may be located in a 200 kb region between the PCNT and PRMT2 genes. The current study aimed to provide insight into the human genome morbidity map of chromosome 21

Autism spectrum disorder, anxiety and severe depression in a male patient with deletion and duplication in the 21q22.3 region: A case report

In this report, a patient carrying a 650 kb deletion and a 759 kb duplication of chromosomal 21q22.3 region was described. Facial dysmorphic features, hypotonia, short stature, learning impairment, autism spectrum disorder, anxiety and depression were observed clinical characteristics. Mentioned copy number variants were the shortest in length reported so far. The current study hypothesized that the presence of a susceptibility locus for autism spectrum disorder associated with depression and anxiety may be located in a 200 kb region between the PCNT and PRMT2 genes. The current study aimed to provide insight into the human genome morbidity map of chromosome 21

Prenatal Diagnosis of Proximal Partial Trisomy 1q Confirmed by Comparative Genomic Hybridization Array: Molecular Cytogenetic Analysis, Fetal Pathology and Review of the Literature

BACKGROUNDPartial trisomy of the long arm of chromosome 1 (1q) is an exceptionally rare chromosomal abnormality and most of the prenatally diagnosed cases are associated with either complete (q11-qter) or large (q21-qter) duplications with pre- or perinatal demise of all reported cases. The most common sonographic findings associated with this karyotype abnormality include ventriculomegaly, increased nuchal translucency or nuchal fold, renal and cardiac abnormalities, craniofacial dysmorphism, and limb deformities. However, there is a wide spectrum of clinical manifestations due to the great variability in the extent of the duplication size and the possible contribution of additional genetic rearrangements in the final phenotype. CASE REPORTWe report on a female fetus with sole partial trisomy 1q presenting with multiple structural malformations in the second trimester scan. Standard karyotyping demonstrated a large duplication on the proximal end of chromosome 1 [46,XX,dup(1)(pterq31::q31q12::q31qter)] and further application of comparative genomic hybridization array confirmed the diagnosis and offered a precise characterization of the genetic defect. CONCLUSIONA fetus with nonmosaic partial trisomy 1q that was prenatally diagnosed upon multiple abnormal ultrasound findings is presented. A detailed review of the currently available literature on the prenatal diagnostic approach of partial trisomy 1q in terms of fetal sonographic assessment and molecular cytogenetic investigation is also provided. The use of novel molecular techniques such comparative genomic hybridization array could shed further light on the correlation between the genes identified in the chromosomal region of interest and the resultant phenotype. Birth Defects Research (Part A) 100:284-293, 2014. (c) 2014 Wiley Periodicals, Inc