Case Reports in Genetics http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. A New Case of 13q12.2q13.1 Microdeletion Syndrome Contributes to Phenotype Delineation Sun, 23 Nov 2014 12:24:33 +0000 http://www.hindawi.com/journals/crig/2014/470830/ A recently described genetic disorder has been associated with 13q12.3 microdeletion spanning three genes, namely, KATNAL1, LINC00426, and HMGB1. Here, we report a new case with similar clinical features that we have followed from birth to 5 years old. The child carried a complex rearrangement with a double translocation: 46,XX,t(7;13)(p15;q14),t(11;15)(q23;q22). Array-CGH identified a de novo microdeletion at 13q12.2q13.1 spanning 3–3.4 Mb and overlapping 13q12.3 critical region. Clinical features resembling those reported in the literature confirm the existence of a distinct 13q12.3 microdeletion syndrome and provide further evidence that is useful to characterize its phenotypic expression during the 5 years of development. Giorgia Mandrile, Eleonora Di Gregorio, Alessandro Calcia, Alessandro Brussino, Enrico Grosso, Elisa Savin, Daniela Francesca Giachino, and Alfredo Brusco Copyright © 2014 Giorgia Mandrile et al. All rights reserved. Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies Thu, 20 Nov 2014 11:38:51 +0000 http://www.hindawi.com/journals/crig/2014/946010/ Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22) gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis. Sun-Mi Cho, Bo Young Hong, Yoonjung Kim, Sang Guk Lee, Jin-Young Yang, Juwon Kim, and Kyung-A Lee Copyright © 2014 Sun-Mi Cho et al. All rights reserved. A Case of Acute Myeloid Leukemia with a Previously Unreported Translocation (14; 15) (q32; q13) Tue, 11 Nov 2014 06:39:39 +0000 http://www.hindawi.com/journals/crig/2014/921240/ Background. We hereby describe what we believe to be the first reported case of t (14; 15) (q32; q13) associated with acute myeloid leukemia (AML). Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia) with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD) mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin) and achieved complete remission after a second induction with high-dose cytarabine (HiDAC) followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15) (q32; q13), while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected). She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15) (q32; q13), this newly reported translocation may be associated with refractory disease. Mohamad Khawandanah, Bradley Gehrs, Shibo Li, Jennifer Holter Chakrabarty, and Mohamad Cherry Copyright © 2014 Mohamad Khawandanah et al. All rights reserved. Atypical Association of Angelman Syndrome and Klinefelter Syndrome in a Boy with 47,XXY Karyotype and Deletion 15q11.2-q13 Tue, 14 Oct 2014 09:38:15 +0000 http://www.hindawi.com/journals/crig/2014/517091/ Angelman syndrome (AS, OMIM 105830) is a neurogenetic disorder with firm clinical diagnostic guidelines, characterized by severe developmental delay and speech impairment, balanced and behavioral disturbance as well as microcephaly, seizures, and a characteristic electroencephalogram (EEG). The majority of AS cases (70%) are caused by a 15q11.2-q13 deletion on the maternally derived chromosome. The frequency of AS has been estimated to be between 1/10000 and 1/20000. Klinefelter syndrome (KS) occurs due to the presence of an extra X chromosome (karyotype 47,XXY). The main features in KS are small testes, hypergonadotropic hypogonadism, gynecomastia, learning difficulties, and infertility. We present what is, to our knowledge, the first case of a patient with both KS and AS due to a 15q11.2-q13 deletion on the maternally derived chromosome and an extra X chromosome of paternal origin. He showed dysmorphic features, axial hypotonia, and delayed acquisition of motor skills. Early diagnosis is essential for optimal treatment of AS children; this is one of the earliest diagnosed cases of AS probably due to the presence of two syndromes. Clinical findings in this patient here described may be helpful to identify any other cases and to evaluate recurrence risks in these families. Javier Sánchez, Ana Peciña, Olga Alonso-Luengo, Antonio González-Meneses, Rocío Vázquez, Guillermo Antiñolo, and Salud Borrego Copyright © 2014 Javier Sánchez et al. All rights reserved. Alsin Related Disorders: Literature Review and Case Study with Novel Mutations Sun, 14 Sep 2014 08:39:07 +0000 http://www.hindawi.com/journals/crig/2014/691515/ Mutations in the ALS2 gene cause three distinct disorders: infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and autosomal recessive juvenile amyotrophic lateral sclerosis. We present a review of the literature and the case of a 16-year-old boy who is, to the best of our knowledge, the first Portuguese case with infantile ascending hereditary spastic paraplegia. Clinical investigations included sequencing analysis of the ALS2 gene, which revealed a heterozygous mutation in exon 5 (c.1425_1428del p.G477Af19) and a heterozygous and previously unreported variant in exon 3 (c.145G>A p.G49R). We also examined 42 reported cases on the clinical characteristics and neurophysiological and imaging studies of patients with known ALS2 gene mutations sourced from PubMed. This showed that an overlap of phenotypic manifestations can exist in patients with infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis. Filipa Flor-de-Lima, Mafalda Sampaio, Nahid Nahavandi, Susana Fernandes, and Miguel Leão Copyright © 2014 Filipa Flor-de-Lima et al. All rights reserved. Preaxial Polydactyly of the Foot: Variable Expression of Trisomy 13 in a Case from Central Africa Mon, 01 Sep 2014 00:00:00 +0000 http://www.hindawi.com/journals/crig/2014/365031/ Trisomy 13 is a chromosomal disorder characterized by a severe clinical picture of multiple congenital anomalies. We here describe the clinical and genetic features and prognosis observed in a newborn with trisomy 13 from Central Africa. He presented the rare feature of preaxial polydactyly of the feet. Sébastien Mbuyi-Musanzayi, Aimé Lumaka, Bienvenu Yogolelo Asani, Toni Lubala Kasole, Prosper Lukusa Tshilobo, Prosper Kalenga Muenze, François Tshilombo Katombe, and Koenraad Devriendt Copyright © 2014 Sébastien Mbuyi-Musanzayi et al. All rights reserved. Pheochromocytoma in a Twelve-Year-Old Girl with SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome Tue, 19 Aug 2014 07:22:12 +0000 http://www.hindawi.com/journals/crig/2014/273423/ A twelve-year-old girl presented with a history of several weeks of worsening headaches accompanied by flushing and diaphoresis. The discovery of markedly elevated blood pressure and tachycardia led the child’s pediatrician to consider the diagnosis of a catecholamine-secreting tumor, and an abdominal CT scan confirmed the presence of a pheochromocytoma. The patient was found to have a mutation in the succinyl dehydrogenase B (SDHB) gene, which is causative for SDHB-related hereditary paraganglioma-pheochromocytoma syndrome. Herein, we describe her presentation and medical management and discuss the clinical implications of SDHB deficiency. Daryl Graham, Megan Gooch, Zhan Ye, Edward Richer, Aftab Chishti, Elizabeth Reilly, and John D’Orazio Copyright © 2014 Daryl Graham et al. All rights reserved. Novel Mutation in the PKHD1 Gene Diagnosed Prenatally in a Fetus with Autosomal Recessive Polycystic Kidney Disease Sun, 13 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/crig/2014/517952/ We report a 29-year-old gravida 2, para 0100, who presented at 19 weeks and 4 days of gestation for ultrasound to assess fetal anatomy. Routine midtrimester fetal anatomy ultrasound revealed enlarged, hyperechoic fetal kidneys and normal amniotic fluid index. Follow-up ultrasound at 23 weeks and 5 days revealed persistently enlarged, hyperechoic fetal kidneys. Progressive oligohydramnios was not evident until 29 weeks of gestation, with anhydramnios noted by 35 weeks of gestation. Amniocentesis was performed for karyotype and to search for mutations in the PKHD1 for the presumptive diagnosis of autosomal recessive polycystic kidney disease (ARPKD). In our patient, a maternally inherited, previously reported pathogenic missense mutation in the PKHD1 gene, c.10444C>T, was identified. A second, previously unreported de novo mutation, c.5909-2delA, was also identified. This mutation affects the canonical splice site and is most likely pathogenic. Our case highlights PKHD1 allelic heterogeneity and the importance of genetic testing in the prenatal setting where many other genetic etiologies can phenocopy ARPKD. Pankaj Thakur, Paul Speer, and Aleksandar Rajkovic Copyright © 2014 Pankaj Thakur et al. All rights reserved. Concomitant Alpha- and Gamma-Sarcoglycan Deficiencies in a Turkish Boy with a Novel Deletion in the Alpha-Sarcoglycan Gene Sun, 22 Jun 2014 12:19:09 +0000 http://www.hindawi.com/journals/crig/2014/248561/ Limb-girdle muscular dystrophy type 2D (LGMD-2D) is caused by autosomal recessive defects in the alpha-sarcoglycan gene located on chromosome 17q21. In this study, we present a child with alpha-sarcoglycanopathy and describe a novel deletion in the alpha-sarcoglycan gene. A 5-year-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally, and a negative molecular test for the dystrophin gene. Muscle biopsy showed dystrophic features. Immunohistochemistry showed that there was diminished expression of alpha- and gamma-sarcoglycans. DNA analysis revealed a novel 7 bp homozygous deletion in exon 3 of the alpha-sarcoglycan gene. His parents were consanguineous heterozygous carriers of the same deletion. We believe this is the first confirmed case of primary alpha-sarcoglycanopathy with a novel deletion in Turkey. In addition, this study demonstrated that both muscle biopsy and DNA analysis remain important methods for the differential diagnosis of muscular dystrophies because dystrophinopathies and sarcoglycanopathies are so similar. Gulden Diniz, Hulya Tosun Yildirim, Sarenur Gokben, Gul Serdaroglu, Filiz Hazan, Kanay Yararbas, and Ajlan Tukun Copyright © 2014 Gulden Diniz et al. All rights reserved. Complex Variant of Philadelphia Translocation Involving Chromosomes 9, 12, and 22 in a Case with Chronic Myeloid Leukaemia Wed, 18 Jun 2014 10:29:39 +0000 http://www.hindawi.com/journals/crig/2014/691630/ Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder included in the broader diagnostic category of myeloproliferative neoplasms, associated with fusion by BCR gene at chromosome 22q11 to ABL1 gene at chromosome 9q34 with the formation of the Philadelphia (Ph) chromosome. In 2–10% of CML cases, the fusion gene arises in connection with a variant translocation, involving chromosomes 9, 22, and one or more different chromosomes; consequently, the Ph chromosome could be masked within a complex chromosome rearrangement. In cases with variant Ph translocation a deletion on der(9) may be more frequently observed than in cases with the classical one. Herein we describe a novel case of CML with complex variant Ph translocation involving chromosomes 9, 12, and 22. We present the hematologic response and cytogenetic response after Imatinib treatment. We also speculated the mechanism which had originated the chromosome rearrangement. F. Malvestiti, C. Agrati, S. Chinetti, A. Di Meco, S. Cirrincione, M. Oggionni, B. Grimi, F. Maggi, G. Simoni, and F. R. Grati Copyright © 2014 F. Malvestiti et al. All rights reserved. Clinical Report of a 17q12 Microdeletion with Additionally Unreported Clinical Features Mon, 02 Jun 2014 06:16:15 +0000 http://www.hindawi.com/journals/crig/2014/264947/ Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tall-appearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified a de novo suspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband’s phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient’s unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations. Jennifer L. Roberts, Stephanie K. Gandomi, Melissa Parra, Ira Lu, Chia-Ling Gau, Majed Dasouki, and Merlin G. Butler Copyright © 2014 Jennifer L. Roberts et al. All rights reserved. Intrauterine Growth Retardation Fetus with Trisomy 16 Mosaicism Wed, 14 May 2014 00:00:00 +0000 http://www.hindawi.com/journals/crig/2014/739513/ Fetal trisomy 16 is considered uniformly lethal early in gestation. It has been reported to be associated with the variability of clinical features and outcomes. Mosaic trisomy 16 leads to a high risk of abnormality in prenatal cases. Intrauterine growth retardation (IUGR) is a common outcome of mosaic trisomy 16. Herein, we report on the case of Thai male IUGR fetus with trisomy 16 mosaicism. The fetal body was too small. Postmortem investigation of placenta revealed the abnormality including small placenta with furcated cord insertion and single umbilical cord artery. Cytogenetic study demonstrated trisomy 16 that was found 100% in placenta and only 16% in the fetal heart while other organs had normal karyotype. In addition, cardiac and other internal organs examination revealed normal morphology. Takol Chareonsirisuthigul, Suchin Worawichawong, Rachanee Parinayok, Patama Promsonthi, and Budsaba Rerkamnuaychoke Copyright © 2014 Takol Chareonsirisuthigul et al. All rights reserved. A Rare, Recurrent, De Novo 14q32.2q32.31 Microdeletion of 1.1 Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability Sun, 30 Mar 2014 11:42:34 +0000 http://www.hindawi.com/journals/crig/2014/530134/ We present a 20-year-old female patient from Indonesia with intellectual disability (ID), proportionate short stature, motor delay, feeding problems, microcephaly, facial dysmorphism, and precocious puberty who was previously screened normal for conventional karyotyping, fragile X testing, and subtelomeric MLPA analysis. Subsequent genome wide array analysis was performed on DNA from blood and revealed a 1.1 Mb deletion in 14q32.2q32.31 (chr14:100,388,343-101,506,214; hg19). Subsequent carrier testing in the parents by array showed that the deletion had occurred de novo in the patient and that her paternal 14q32 allele was deleted. The deleted region encompasses the DLK1/GTL2 imprinted gene cluster which is consistent with the maternal UPD(14)-like phenotype of the patient. This rare, recurrent microdeletion was recently shown not to be mediated by low copy repeats, but by expanded TGG repeats, flanking the 14q32.2q32.21 deletion boundaries, a novel mechanism of recurrent genomic rearrangement. This is another example how the application of high resolution genome wide testing provides an accurate genetic diagnosis, thereby improving the care for patients and optimizing the counselling for family. Almira Zada, Farmaditya E. P. Mundhofir, Rolph Pfundt, Nico Leijsten, Willy Nillesen, Sultana M. H. Faradz, and Nicole de Leeuw Copyright © 2014 Almira Zada et al. All rights reserved. A Turner Syndrome Patient Carrying a Mosaic Distal X Chromosome Marker Mon, 17 Mar 2014 16:21:46 +0000 http://www.hindawi.com/journals/crig/2014/597314/ A skin sample from a 17-year-old female was received for routine karyotyping with a set of clinical features including clonic seizures, cardiomyopathy, hepatic adenomas, and skeletal dysplasia. Conventional karyotyping revealed a mosaic Turner syndrome karyotype with a cell line containing a small marker of X chromosome origin. This was later confirmed on peripheral blood cultures by conventional G-banding, fluorescence in situ hybridisation and microarray analysis. Similar Turner mosaic marker chromosome cases have been previously reported in the literature, with a variable phenotype ranging from the mild “classic” Turner syndrome to anencephaly, agenesis of the corpus callosum, complex heart malformation, and syndactyly of the fingers and toes. This case report has a phenotype that is largely discordant with previously published cases as it lies at the severe end of the Turner variant phenotype scale. The observed cytogenetic abnormalities in this study may represent a coincidental finding, but we cannot exclude the possibility that the marker has a nonfunctioning X chromosome inactivation locus, leading to functional disomy of those genes carried by the marker. Roberto L. P. Mazzaschi, Juliet Taylor, Stephen P. Robertson, Donald R. Love, and Alice M. George Copyright © 2014 Roberto L. P. Mazzaschi et al. All rights reserved. Neurofibromatosis Type 1: A Novel NF1 Mutation Associated with Mitochondrial Complex I Deficiency Tue, 04 Mar 2014 12:49:50 +0000 http://www.hindawi.com/journals/crig/2014/423071/ Background. Neurofibromatosis type 1 is a multisystemic, progressive disease, with an estimated incidence of 1/3500-2500. Mitochondrial diseases are generally multisystemic and may be present at any age, and the global prevalence is 1/8500. The diagnosis of these disorders is complex because of its clinical and genetic heterogeneity. Case Report. We present a rare case of the association of these two different genetic diseases, in which a heterozygous missense mutation in the NF1 gene was identified which had not yet been described (p.M1149 V). Additionally, the patient is suspected of carrying an unspecified mutation causing respiratory chain complex I deficiency. Clinical presentation included hypotonia, global development delay, reduced growth rate, progressive microcephaly, and numerous café-au-lait spots. Discussion. To the best of our knowledge this is the first report of complex I deficiency in a patient with neurofibromatosis type 1. It is very important to maintain a high index of suspicion for the diagnosis of mitochondrial disorders. In this patient, both the laboratory screening and muscle histology were normal and only the biochemical study of muscle allowed us to confirm the diagnosis. Sara Domingues, Lara Isidoro, Dalila Rocha, and Jorge Sales Marques Copyright © 2014 Sara Domingues et al. All rights reserved. Novel SMAD3 Mutation in a Patient with Hypoplastic Left Heart Syndrome with Significant Aortic Aneurysm Mon, 03 Mar 2014 15:52:07 +0000 http://www.hindawi.com/journals/crig/2014/591516/ Aneurysms-osteoarthritis syndrome (AOS) caused by haploinsufficiency of SMAD3 is a recently described cause of syndromic familial thoracic aortic aneurysm and dissection (TAAD). We identified a novel SMAD3 mutation in a patient with hypoplastic left heart syndrome (HLHS) who developed progressive aortic aneurysm requiring surgical replacement of the neoaortic root, ascending aorta, and proximal aortic arch. Family screening for the mutation revealed that his father, who has vascular and skeletal features of AOS, and his brother, who is asymptomatic, also have the pathogenic mutation. This is the first case report of a SMAD3 mutation in a patient with hypoplastic left heart syndrome. This case highlights the importance of genetic testing for known causes of aneurysm in patients with congenital heart disease who develop aneurysmal disease as it may significantly impact the management of those patients and their family members. Kristi K. Fitzgerald, Abdul Majeed Bhat, Katrina Conard, James Hyland, and Christian Pizarro Copyright © 2014 Kristi K. Fitzgerald et al. All rights reserved. Previously Unreported Chromosomal Aberrations of t(3;3)(q29;q23), t(4;11)(q21;q23), and t(11;18)(q10;q10) in a Patient with Accelerated Phase Ph+ CML Sun, 23 Feb 2014 00:00:00 +0000 http://www.hindawi.com/journals/crig/2014/582016/ Chronic myelogenous leukemia (CML) is a clonal hematological disorder, which is characterized by the presence of the classical or variant Philadelphia translocations. During the progression to blastic phase of the disease secondary chromosomal abnormalities may emerge. Such secondary chromosomal abnormalities are nonrandom, the more frequent ones being trisomy 8 and 19, supernumerary i(17q), and extra Philadelphia chromosomes. Furthermore, a minor percentage of the patients may acquire different secondary chromosomal abnormalities including translocations between other chromosomes. We report here a patient with Ph+ CML presenting secondary chromosomal abnormalities including t(4;11)(q21;q23), t(3;3)(q29;q23) and t(11;18)(q10;q10) during the course of CML progression. Cigdem Aydin, Zafer Cetin, Ozan Salim, Orhan Kemal Yucel, Levent Undar, and Sibel Berker Karauzum Copyright © 2014 Cigdem Aydin et al. All rights reserved. Microduplication of 3p26.3 Implicated in Cognitive Development Thu, 13 Feb 2014 12:10:45 +0000 http://www.hindawi.com/journals/crig/2014/295359/ We report here a 34-month-old boy with global developmental delay referred for molecular karyotyping and fragile X studies. Molecular karyotype analysis revealed a microduplication in the 3p26.3 region involving part of the CHL1 and CNTN6 genes. Several deletions, one translocation, and one duplication have previously been described in this region of chromosome 3. The CHL1 gene has been proposed as a dosage-sensitive gene with a central role in cognitive development, and so the microduplication reported here appears to be implicated in our patient’s phenotype. Leah Te Weehi, Raj Maikoo, Adrian Mc Cormack, Roberto Mazzaschi, Fern Ashton, Liangtao Zhang, Alice M. George, and Donald R. Love Copyright © 2014 Leah Te Weehi et al. All rights reserved. Congenital Arthrogryposis: An Extension of the 15q11.2 BP1-BP2 Microdeletion Syndrome? Wed, 12 Feb 2014 12:42:01 +0000 http://www.hindawi.com/journals/crig/2014/127258/ The proximal 15q11–q13 region contains 5 breakpoints (BP1–BP5). The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes. The genes in this region are known to play a role in central nervous system development and/or function. Microdeletions within the 15q11.2 BP1-BP2 region have been reported in patients with neurological dysfunction, developmental delays, behavioral problems, and dysmorphic features. We report two unrelated subjects with the 15q11.2 BP1-BP2 microdeletion and presenting with congenital arthrogryposis, a feature which has not been previously reported as part of this newly recognized microdeletion syndrome. While arthrogryposis seen in these two subjects may be coincidental, we propose that congenital arthrogryposis may result from neurological dysfunction and involvement of the microdeletion of the 15q11.2 BP1-BP2 region, further expanding the phenotype of this microdeletion syndrome. We encourage others to report patients with this chromosome microdeletion and neurological findings to further characterize the clinical phenotype. K. M. Usrey, C. A. Williams, M. Dasouki, L. C. Fairbrother, and M. G. Butler Copyright © 2014 K. M. Usrey et al. All rights reserved. A Paternally Inherited BRCA1 Mutation Associated with an Unusual Aggressive Clinical Phenotype Mon, 10 Feb 2014 09:30:39 +0000 http://www.hindawi.com/journals/crig/2014/875029/ This report highlights the necessity of genetic testing, at least for BRCA1 mutations, of young females diagnosed with triple negative breast cancer, even in the absence of or limited family history. A 34-year-old female with a locally advanced, triple negative tumour, which perforated the skin, is described. At the time of diagnosis, the patient had already multiple lung metastases and although chemotherapy was started immediately, she died with rapid systemic disease progression. The patient was found to carry the BRCA1 p.E1060X mutation, which is located on exon 11 of the gene. The high penetrance of BRCA1 gene is not represented in the patient’s family, since the mutation was paternally inherited. It is evident that females belonging to small families, along with paternal inheritance of pathogenic BRCA mutations that predispose for breast cancer, in most cases will probably be genetically tested only after being diagnosed with cancer. Florentia Fostira, Nikolaos Tsoukalas, Irene Konstantopoulou, Vassilios Georgoulias, Charalambos Christophyllakis, and Drakoulis Yannoukakos Copyright © 2014 Florentia Fostira et al. All rights reserved. An Interstitial Deletion at 10q26.2q26.3 Thu, 06 Feb 2014 16:14:34 +0000 http://www.hindawi.com/journals/crig/2014/505832/ We present a case of an interstitial subtelomeric 10q26 deletion in a male child with moderate developmental delay and minor dysmorphic features. Using array comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), we have detected an interstitial deletion at 10q26.2q26.3 encompassing a 5.8 Mb region and spanning 24 genes. Interestingly, losses of this chromosome 10 region have not been previously associated with a phenotype outcome. According to an in silico evaluation, we have suggested that PPP2R2D and BNIP3 losses are likely a cause of developmental delay in the index patient. Our data allow to speculating that haploinsufficiency of these two genes in 10q26.3, which is usually ignored in the context of chromosome 10q deletions, has a phenotypic effect. Ivan Y. Iourov, Svetlana G. Vorsanova, Oxana S. Kurinnaia, and Yuri B. Yurov Copyright © 2014 Ivan Y. Iourov et al. All rights reserved. Apparent Homozygosity of p.Phe508del in CFTR due to a Large Gene Deletion of Exons 4–11 Thu, 06 Feb 2014 16:08:45 +0000 http://www.hindawi.com/journals/crig/2014/613863/ We report a classic cystic fibrosis (CF) boy with a large deletion of exons 4–11 in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on one allele and p.Phe508del in exon 10 on the second allele. Both parents of Georgian and Ukrainian background had no personal or family history of the disease. The initial molecular diagnostic investigation identified the patient as homozygous for the p.Phe508del and not compatible with his parent’s genetic status. The possibility of nonpaternity or uniparental disomy (UPD7) was investigated and excluded using microsatellite analysis of highly polymorphic markers on chromosome 7. Array-CGH was also performed on the patient and revealed a male profile with a subtle deletion within the CFTR gene on the long arm (q-arm) of chromosome 7 (7q31.2). The deletion was confirmed by MLPA extending from probe L02380 to probe L14978 (28.7 kb) and that was inherited from his father, while p.PheF508del was inherited from his mother. These data highlight the need for additional testing for large deletions in patients with apparent homozygosity for a mutated CFTR allele that do not match the carrier status of the parents. Not testing can lead to misdiagnosis and misinterpretation of mutation carrier status and the expected penetrance of the disorder. Vassos Neocleous, Panayiotis K. Yiallouros, George A. Tanteles, Constantina Costi, Maria Moutafi, Phivos Ioannou, Philippos C. Patsalis, Carolina Sismani, and Leonidas A. Phylactou Copyright © 2014 Vassos Neocleous et al. All rights reserved. A Case of 17q21.31 Microduplication and 7q31.33 Microdeletion, Associated with Developmental Delay, Microcephaly, and Mild Dysmorphic Features Tue, 04 Feb 2014 14:11:47 +0000 http://www.hindawi.com/journals/crig/2014/658570/ Concurrent cryptic microdeletion and microduplication syndromes have recently started to reveal themselves with the advent of microarray technology. Analysis has shown that low-copy repeats (LCRs) have allowed chromosome regions throughout the genome to become hotspots for nonallelic homologous recombination to take place. Here, we report a case of a 7.5-year-old girl who manifests microcephaly, developmental delay, and mild dysmorphic features. Microarray analysis identified a microduplication in chromosome 17q21.31, which encompasses the CRHR1, MAPT, and KANSL1 genes, as well as a microdeletion in chromosome 7q31.33 that is localised within the GRM8 gene. To our knowledge this is one of only a few cases of 17q21.31 microduplication. The clinical phenotype of patients with this microduplication is milder than of those carrying the reciprocal microdeletions, and suggests that the lower incidence of the former compared to the latter may be due to underascertainment. Adrian Mc Cormack, Juliet Taylor, Leah Te Weehi, Donald R. Love, and Alice M. George Copyright © 2014 Adrian Mc Cormack et al. All rights reserved. A Case of False Negative NIPT for Down Syndrome-Lessons Learned Tue, 04 Feb 2014 09:14:17 +0000 http://www.hindawi.com/journals/crig/2014/823504/ Down syndrome or trisomy 21 is the most common cause of prenatal chromosome abnormalities with approximately 50% of all reported chromosome conditions. With the successful introduction of noninvasive prenatal testing (NIPT) for Down syndrome into routine prenatal care, it is important to understand the risks, benefits, and limitations in order to guide patients in making an informed decision. Herein, we describe the first published case report of a patient whose fetus tested “negative” for Trisomy 21 by NIPT but was diagnosed postnatally with trisomy 21. We present the importance of proper pretest and posttest genetic counseling to ensure prenatal patients are able to make informed decisions and are educated appropriately about NIPT. Meagan Smith, Kimberly M. Lewis, Alexandrea Holmes, and Jeannie Visootsak Copyright © 2014 Meagan Smith et al. All rights reserved. Monosomy 21 Seen in Live Born Is Unlikely to Represent True Monosomy 21: A Case Report and Review of the Literature Tue, 04 Feb 2014 07:21:12 +0000 http://www.hindawi.com/journals/crig/2014/965401/ We report a case of a neonate who was shown with routine chromosome analysis on peripheral blood lymphocytes to have full monosomy 21. Further investigation on fibroblast cells using conventional chromosome and FISH analysis revealed two additional mosaic cell lines; one is containing a ring chromosome 21 and the other a double ring chromosome 21. In addition, chromosome microarray analysis (CMA) on fibroblasts showed a mosaic duplication of chromosome region 21q11.2q22.13 with approximately 45% of cells showing three copies of the proximal long arm segment, consistent with the presence of a mosaic ring chromosome 21 with ring instability. The CMA also showed complete monosomy for an 8.8 Mb terminal segment (21q22.13q22.3). Whilst this patient had a provisional clinical diagnosis of trisomy 21, the patient also had phenotypic features consistent with monosomy 21, such as prominent epicanthic folds, broad nasal bridge, anteverted nares, simple ears, and bilateral overlapping fifth fingers, features which can also be present in individuals with Down syndrome. The patient died at 4.5 months of age. This case highlights the need for additional studies using multiple tissue types and molecular testing methodologies in patients provisionally diagnosed with monosomy 21, in particular if detected in the neonatal period. Trent Burgess, Lilian Downie, Mark D. Pertile, David Francis, Melissa Glass, Sara Nouri, and Rosalynn Pszczola Copyright © 2014 Trent Burgess et al. All rights reserved. Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy Mon, 03 Feb 2014 07:32:02 +0000 http://www.hindawi.com/journals/crig/2014/508231/ Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in the LMNA gene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of the LMNA gene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD) analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3–q22 region flanking the LMNA locus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient. Shaochun Bai, Anthony Lozada, Marilyn C. Jones, Harry C. Dietz, Melissa Dempsey, and Soma Das Copyright © 2014 Shaochun Bai et al. All rights reserved. An Active Isodicentric X Chromosome in a Case of Refractory Anaemia with Ring Sideroblasts Associated with Marked Thrombocytosis Thu, 30 Jan 2014 09:17:42 +0000 http://www.hindawi.com/journals/crig/2014/205318/ Refractory anaemia with ring sideroblasts and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organization (WHO) classification. It displays features characteristic of both myelodysplastic syndrome and myeloproliferative neoplasia plus ring sideroblasts ≥15% and marked thrombocytosis. Most patients with RARS-T show a normal karyotype. We report a 76-year-old woman diagnosed with RARS-T (76% of ring sideroblasts) with JAK2 (V617F) mutation and a load of 30–40%. Classical and molecular cytogenetic (FISH) studies of a bone marrow sample revealed the presence of isodicentric X chromosome [(idic(X)(q13)]. Moreover, HUMARA assay showed the idic(X)(q13) as the active X chromosome. This finding was correlated with the cytochemical finding of ring sideroblasts. To our knowledge, this is the first reported case of an active isodicentric X in a woman with RARS-T. Rosario M. Morales Camacho, Javier Sanchez, Irene Marcos Luque, Ricardo Bernal, Jose F Falantes, and Jose A Pérez-Simón Copyright © 2014 Rosario M. Morales Camacho et al. All rights reserved. First Birth after Sperm Selection through Discontinuous Gradient Centrifugation and Artificial Insemination from a Chromosomal Translocation Carrier Thu, 23 Jan 2014 16:37:42 +0000 http://www.hindawi.com/journals/crig/2014/906145/ Introduction. Balanced chromosomal carriers, though usually healthy, are confronted with recurrent spontaneous abortions and malformations in the offspring. Those are related to the transmission of an abnormal, chromosomally unbalanced genotype. We evidenced that the proportion of unbalanced spermatozoa can be significantly decreased through a sperm preparation process called discontinuous gradient centrifugation (DGC). We therefore started offering intrauterine inseminations with this procedure to couples with a male translocation carriers. Case Presentation. We report the case of a 37-year-old man carrying a t(3;10)(q25;p13) reciprocal translocation. He and his partner had had trouble conceiving for ten years and had four spontaneous abortions. DGC in this patient decreased the proportion of unbalanced spermatozoa from 63.6% to 52.3%. They were therefore offered intrauterine insemination with DGC, which eventually led to the birth of a healthy female child carrying the paternal translocation. Conclusion. We showed that translocation carriers could be offered intrauterine inseminations with DGC. Before this, the only two options were natural conception with prenatal diagnosis and termination of chromosomally unbalanced fetuses or preimplantation genetic diagnosis, which is a much heavier and costly procedure. We are currently offering this option through a multicentric program in France, and this is the first birth originating from it. Alexandre Rouen, Capucine Hyon, Richard Balet, Nicole Joyé, Nino Guy Cassuto, and Jean-Pierre Siffroi Copyright © 2014 Alexandre Rouen et al. All rights reserved. Warfarin Dosing in a Patient with CYP2C9*3*3 and VKORC1-1639 AA Genotypes Wed, 22 Jan 2014 00:00:00 +0000 http://www.hindawi.com/journals/crig/2014/413743/ Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations in CYP2C9 and VKORC1 are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes of CYP2C9*3*3 and VKORC1-1639 AA. Warfarin dosing was subsequently restarted and stabilized at 0.5 mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events. Mark Johnson, Craig Richard, Renee Bogdan, and Robert Kidd Copyright © 2014 Mark Johnson et al. All rights reserved. Rhabdomyolysis and Cardiomyopathy in a 20-Year-Old Patient with CPT II Deficiency Sun, 19 Jan 2014 14:07:14 +0000 http://www.hindawi.com/journals/crig/2014/496410/ Aim. To raise the awareness of adult-onset carnitite palmitoyltransferase II deficiency (CPT II) by describing clinical, biochemical, and genetic features of the disease occurring in early adulthood. Method. Review of the case characteristics and literature review. Results. We report on a 20-year-old man presenting with dyspnea, fatigue, fever, and myoglobinuria. This was the second episode with such symptoms (the previous one being three years earlier). The symptoms occurred after intense physical work, followed by a viral infection resulting in fever treated with NSAIDs. Massive rhabdomyolysis was diagnosed, resulting in acute renal failure necessitating plasmapheresis and hemodialysis, acute hepatic lesion, and respiratory insufficiency. Additionally, our patient had cardiomyopathy with volume overload. After a detailed workup, CPT II deficiency was suspected. We did a sequencing analysis for exons 1, 3, and 4 of the CPT II gene and found that the patient was homozygote for Ser 113 Leu mutation in exon 3 of the CPT II gene. The patient recovery was complete except for the cardiomiopathy with mildly impaired systolic function. Conclusion. Whenever a patient suffers recurrent episodes of myalgia, followed by myoglobinuria due to rhabdomyolysis, we should always consider the possibility of this rare condition. The definitive diagnose of this condition is achieved by genetic testing. M. Vavlukis, A. Eftimov, P. Zafirovska, E. Caparovska, B. Pocesta, S. Kedev, and A. J. Dimovski Copyright © 2014 M. Vavlukis et al. All rights reserved.