Case Reports in Genetics The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome Sat, 30 Apr 2016 07:50:53 +0000 Kleefstra syndrome is characterized by hypotonia, developmental delay, dysmorphic features, congenital heart defects, and so forth. It is caused by 9q34.3 microdeletions or EHMT1 mutations. Herein a 20-month-old girl with Kleefstra syndrome, due to a de novo subterminal deletion, is described. She exhibits a rare and complex cardiopathy, encompassing multiple coronary artery microfistulas, VSD/ASD, and PFO. Euthymia Vargiami, Athina Ververi, Hamda Al-Mutawa, Georgia Gioula, Spyridon Gerou, Fotios Rouvalis, Marios Kambouris, and Dimitrios I. Zafeiriou Copyright © 2016 Euthymia Vargiami et al. All rights reserved. Whole Exome Sequencing Leading to the Diagnosis of Dysferlinopathy with a Novel Missense Mutation (c.959G>C) Tue, 19 Apr 2016 06:03:51 +0000 Dysferlinopathy is an uncommon, progressive muscular dystrophy that has a wide phenotypic variability and primarily supportive management (Nguyen et al., 2007; Narayanaswami et al., 2014). Amyloid myopathy is a distinct, rare disorder that can present similarly to inflammatory myopathies and requires a high clinical suspicion for early intervention to prolong survival. Amyloid myopathy is typically associated with other systemic manifestations of amyloidosis, but rare cases of isolated amyloid myopathy have been described (Mandl et al., 2000; Hull et al., 2001). Positive Congo red stains on tissue biopsy remain the gold standard for diagnosis (Spuler et al., 1998; Karacostas et al., 2005). A high clinical suspicion and meticulous diagnostic workup that includes novel techniques are necessary for identifying these rare disorders. We report a middle-aged man with progressive leg muscle weakness who was initially treated as having amyloid myopathy but was later diagnosed as having dysferlinopathy by Whole Exome Sequencing (WES) analysis. We also report a novel missense mutation (c.959G>C) to help correlate in any patient with presumed dysferlinopathy and to add to the already known genotype of this disorder. Abhisek Swaika, Nicole J. Boczek, Neha Sood, Kimberly Guthrie, Eric W. Klee, Ankit Agrawal, Elliot L. Dimberg, and Sikander Ailawadhi Copyright © 2016 Abhisek Swaika et al. All rights reserved. Novel GLA Deletion in a Cypriot Female Presenting with Cornea Verticillata Wed, 30 Mar 2016 13:20:19 +0000 Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the hydrolytic enzyme α-galactosidase A (α-Gal-A). It is characterized by progressive lysosomal accumulation of globotriaosylceramide (Gb3) and multisystem pathology, affecting the skin, nervous and cerebrovascular systems, kidneys, and heart. Heterozygous females typically exhibit milder symptoms and a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. We report on a 17-year-old female in whom cornea verticillata was found during a routine ophthalmological examination but with no other clinical symptoms. Leucocyte α-galactosidase activity was within the overlap range between Fabry heterozygotes and normal controls. Sanger sequencing of the GLA gene failed to reveal any pathogenic variants. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis revealed a deletion of exon 7. Using a long-range PCR walking approach, we managed to identify the deletion breakpoints. The deletion spans 1182 bp, with its 5′ end located within exon 6 of the GLA gene and its 3′ end located 612 bp downstream of exon 7. This finding represents a novel deletion identified in the first reported Cypriot female carrier of Fabry disease. Theodoros Georgiou, Gavriella Mavrikiou, Angelos Alexandrou, Elena Spanou-Aristidou, Isavella Savva, Theodoros Christodoulides, Maria Krasia, Violetta Christophidou-Anastasiadou, Carolina Sismani, Anthi Drousiotou, and George A. Tanteles Copyright © 2016 Theodoros Georgiou et al. All rights reserved. Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function Wed, 16 Mar 2016 07:27:54 +0000 A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders. STXBP1 mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified a de novo c.1651C>T (p.R551C) mutation in STXBP1. Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature of STXBP1 disease. Dong Li, Elizabeth Bhoj, Elizabeth McCormick, Fengxiang Wang, James Snyder, Tiancheng Wang, Yan Zhao, Cecilia Kim, Rosetta Chiavacci, Lifeng Tian, Marni J. Falk, and Hakon Hakonarson Copyright © 2016 Dong Li et al. All rights reserved. False Negative Cell-Free DNA Screening Result in a Newborn with Trisomy 13 Mon, 22 Feb 2016 07:00:29 +0000 Background. Noninvasive prenatal screening (NIPS) is revolutionizing prenatal screening as a result of its increased sensitivity, specificity. NIPS analyzes cell-free fetal DNA (cffDNA) circulating in maternal plasma to detect fetal chromosome abnormalities. However, cffDNA originates from apoptotic placental trophoblast; therefore cffDNA is not always representative of the fetus. Although the published data for NIPS testing states that the current technique ensures high sensitivity and specificity for aneuploidy detection, false positives are possible due to isolated placental mosaicism, vanishing twin or cotwin demise, and maternal chromosome abnormalities or malignancy. Results. We report a case of false negative cell-free DNA (cfDNA) screening due to fetoplacental mosaicism. An infant male with negative cfDNA screening result was born with multiple congenital abnormalities. Postnatal chromosome and FISH studies on a blood specimen revealed trisomy 13 in 20/20 metaphases and 100% interphase nuclei, respectively. FISH analysis on tissues collected after delivery revealed extraembryonic mosaicism. Conclusions. Extraembryonic tissue mosaicism is likely responsible for the false negative cfDNA screening result. This case illustrates that a negative result does not rule out the possibility of a fetus affected with a trisomy, as cffDNA is derived from the placenta and therefore may not accurately represent the fetal genetic information. Yang Cao, Nicole L. Hoppman, Sarah E. Kerr, Christopher A. Sattler, Kristi S. Borowski, Myra J. Wick, W. Edward Highsmith, and Umut Aypar Copyright © 2016 Yang Cao et al. All rights reserved. De Novo Interstitial Microdeletion at 1q32.1 in a 10-Year-Old Boy with Developmental Delay and Dysmorphism Wed, 03 Feb 2016 09:14:53 +0000 A 10-year-old boy was referred with developmental delay and dysmorphism. Genomewide aCGH microarray analysis detected a de novo 3.7 Mb deletion at 1q32.1: arr 1q32.1(199,985,888-203,690,832)x1 dn [build HG19]. This first report of a deletion in this region implies a critical role for dosage-sensitive genes within 1q32.1 in neurological development. This is consistent with previously reported duplications of this region in patients with a similar phenotype. Jennifer Carter, Melinda Zombor, Adrienn Máté, László Sztriha, and Jonathan J. Waters Copyright © 2016 Jennifer Carter et al. All rights reserved. De Novo Trisomy 1q10q23.3 Mosaicism Causes Microcephaly, Severe Developmental Delay, and Facial Dysmorphic Features but No Cardiac Anomalies Sun, 31 Jan 2016 13:01:01 +0000 Proximal duplications of chromosome 1q are rare chromosomal abnormalities. Most patients with this condition present with neurological, urogenital, and congenital heart disease and short life expectancy. Mosaicism for trisomy 1q10q23.3 has only been reported once in the literature. Here we discuss a second case: a girl with a postnatal diagnosis of a de novo pure mosaic trisomy 1q1023.3 who has no urogenital or cardiac anomalies. Shirley Lo-A-Njoe, Lars T. van der Veken, Clementien Vermont, Louise Rafael-Croes, Vincent Keizer, Ron Hochstenbach, Nine Knoers, and Mieke M. van Haelst Copyright © 2016 Shirley Lo-A-Njoe et al. All rights reserved. Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases Thu, 28 Jan 2016 14:06:43 +0000 Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians. Ho-Ming Luk Copyright © 2016 Ho-Ming Luk. All rights reserved. Osteoporosis-Pseudoglioma in a Mauritanian Child due to a Novel Mutation in LRP5 Tue, 19 Jan 2016 09:15:59 +0000 Osteoporosis-pseudoglioma (OPPG) syndrome is a very rare autosomal recessive disorder, caused by mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. It manifests by severe juvenile osteoporosis with congenital or infancy-onset visual loss. We describe a case of OPPG due to novel mutation in LRP5 gene, occurring in a female Mauritanian child. This 10-year-old female child was born blind, and after then multiple fragility fractures appeared. PCR amplification and sequencing revealed a novel homozygous nonsense mutation in exon 10 of the LRP5 gene (c.2270G>A; ); this mutation leads to the production of a truncated protein containing 757 amino acids instead of 1615, located in the third β-propeller domain of the LRP5 protein. Both parents were heterozygous for the mutation. This is the first case of the OPPG described in black Africans, which broadens the spectrum of LRP5 gene mutations in OPPG. Noura Biha, S. M. Ghaber, M. M. Hacen, and Corinne Collet Copyright © 2016 Noura Biha et al. All rights reserved. A Novel Nonsense Mutation of the AGL Gene in a Romanian Patient with Glycogen Storage Disease Type IIIa Sun, 17 Jan 2016 08:29:29 +0000 Background. Glycogen storage disease type III (GSDIII) is a rare metabolic disorder with autosomal recessive inheritance, caused by deficiency of the glycogen debranching enzyme. There is a high phenotypic variability due to different mutations in the AGL gene. Methods and Results. We describe a 2.3-year-old boy from a nonconsanguineous Romanian family, who presented with severe hepatomegaly with fibrosis, mild muscle weakness, cardiomyopathy, ketotic fasting hypoglycemia, increased transaminases, creatine phosphokinase, and combined hyperlipoproteinemia. GSD type IIIa was suspected. Accordingly, genomic DNA of the index patient was analyzed by next generation sequencing of the AGL gene. For confirmation of the two mutations found, genetic analysis of the parents and grandparents was also performed. The patient was compound heterozygous for the novel mutation c.3235C>T, p.Gln107 (exon 24) and the known mutation c.1589C>G, p.Ser53 (exon 12). c.3235 >T, p.Gln107 was inherited from the father, who inherited it from his mother. c.1589C>G, p.Ser53 was inherited from the mother, who inherited it from her father. Conclusion. We report the first genetically confirmed case of a Romanian patient with GSDIIIa. We detected a compound heterozygous genotype with a novel mutation, in the context of a severe hepatopathy and an early onset of cardiomyopathy. Anca Zimmermann, Heidi Rossmann, Simona Bucerzan, and Paula Grigorescu-Sido Copyright © 2016 Anca Zimmermann et al. All rights reserved. Early Morphokinetic Monitoring of Embryos after Intracytoplasmic Sperm Injection with Fresh Ejaculate Sperm in Nonmosaic Klinefelter Syndrome: A Different Presentation Wed, 30 Dec 2015 09:41:40 +0000 The patient was diagnosed with nonmosaic 47, XXY Klinefelter Syndrome with the AZF deletion absent and SRY+. The nonmosaic 47, XXY karyotype was confirmed on a skin biopsy chromosomal analysis. Using only ejaculate motile sperms, 11 oocytes underwent ICSI and were placed rapidly in a time lapse (Embryoscope ©) with a specific culture dish. Biopsies were performed on six embryos on the 3rd day, and numerical chromosomal abnormalities were observed using the FISH test before transfer. PGS results were normal in only two embryos with normal morphokinetics in the Embryoscope. For clinical confirmation of pregnancy, ultrasonographic examination was performed during the 7th week of pregnancy, and two gestational sacs and fetal heart beat were observed. Ali Sami Gurbuz, Ahmet Salvarci, Necati Ozcimen, and Ayse Gul Zamani Copyright © 2015 Ali Sami Gurbuz et al. All rights reserved. Intermediate MCAD Deficiency Associated with a Novel Mutation of the ACADM Gene: c.1052C>T Tue, 22 Dec 2015 08:22:00 +0000 Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder that leads to a defect in fatty acid oxidation. ACADM is the only candidate gene causing MCAD deficiency. A single nucleotide change, c.985A>G, occurring at exon 11 of the ACADM gene, is the most prevalent mutation. In this study, we report a Caucasian family with multiple MCADD individuals. DNA sequence analysis of the ACADM gene performed in this family revealed that two family members showing mild MCADD symptoms share the same novel change in exon 11, c.1052C>T, resulting in a threonine-to-isoleucine change. The replacement is a nonconservative amino acid change that occurs in the C-terminal all-alpha domain of the MCAD protein. Here we report the finding of a novel missense mutation, c.1052C>T (p.Thr326Ile), in the ACADM gene. To our knowledge, c.1052C>T has not been previously reported in the literature or in any of the current databases we utilize. We hypothesize that this particular mutation in combination with p.Lys304Glu results in an intermediate clinical phenotype of MCADD. Holli M. Drendel, Jason E. Pike, Katherine Schumacher, Karen Ouyang, Jing Wang, Mary Stuy, Stephen Dlouhy, and Shaochun Bai Copyright © 2015 Holli M. Drendel et al. All rights reserved. Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene Thu, 03 Dec 2015 14:04:34 +0000 A novel RFX6 homozygous missense mutation was identified in an infant with Mitchell-Riley syndrome. The most common features of Mitchell-Riley syndrome were present, including severe neonatal diabetes associated with annular pancreas, intestinal malrotation, gallbladder agenesis, cholestatic disease, chronic diarrhea, and severe intrauterine growth restriction. Perijejunal tissue similar to pancreatic tissue was found in the submucosa, a finding that has not been previously reported in this syndrome. This case associating RFX6 mutation with structural and functional pancreatic abnormalities reinforces the RFX6 gene role in pancreas development and β-cell function, adding information to the existent mutation databases. Marta Zegre Amorim, Jayne A. L. Houghton, Sara Carmo, Inês Salva, Ana Pita, and Luis Pereira-da-Silva Copyright © 2015 Marta Zegre Amorim et al. All rights reserved. The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome Tue, 17 Nov 2015 08:58:58 +0000 Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified. Molly B. Sheridan, Elizabeth Wohler, Denise A. S. Batista, Carolyn Applegate, and Julie Hoover-Fong Copyright © 2015 Molly B. Sheridan et al. All rights reserved. Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis Wed, 11 Nov 2015 11:22:46 +0000 Objectives. Although hereditary neuropathy with liability to pressure palsies (HNPP) presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes. Case Report. In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment. Conclusions. HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein. Martin Gencik and Josef Finsterer Copyright © 2015 Martin Gencik and Josef Finsterer. All rights reserved. Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1 Mon, 26 Oct 2015 11:46:37 +0000 We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the and mutations and demonstrate the utility of WES in cases with unclear diagnoses. Jessie C. Jacobsen, Emma Glamuzina, Juliet Taylor, Brendan Swan, Shona Handisides, Callum Wilson, Michael Fietz, Tessa van Dijk, Bart Appelhof, Rosamund Hill, Rosemary Marks, Donald R. Love, Stephen P. Robertson, Russell G. Snell, and Klaus Lehnert Copyright © 2015 Jessie C. Jacobsen et al. All rights reserved. Progressive Lower Extremity Weakness and Axonal Sensorimotor Polyneuropathy from a Mutation in KIF5A (c.611G>A;p.Arg204Gln) Mon, 12 Oct 2015 07:37:40 +0000 Introduction. Hereditary Spastic Paraplegia (HSP) is a rare hereditary disorder that primarily involves progressive spasticity of the legs (hamstrings, quadriceps, and calves). Methods. A 27-year-old gentleman was a fast runner and able to play soccer until age 9 when he developed slowly progressive weakness. He was wheelchair-bound by age 25. He was evaluated by laboratory testing, imaging, electrodiagnostics, and molecular genetics. Results. Electrodiagnostic testing revealed an axonal sensorimotor polyneuropathy. Genetic testing for HSP in 2003 was negative; repeat testing in 2013 revealed a mutation in KIF5A (c.611G>A;p.Arg204Gln). Conclusions. A recent advance in neurogenetics has allowed for more genes and mutations to be identified; over 76 different genetic loci for HSP and 59 gene products are currently known. Even though our patient had a sensorimotor polyneuropathy on electrodiagnostic testing and a 2003 HSP genetic panel that was negative, a repeat HSP genetic panel was performed in 2013 due to the advancement in neurogenetics. This revealed a mutation in KIF5A. Nivedita U. Jerath, Tiffany Grider, and Michael E. Shy Copyright © 2015 Nivedita U. Jerath et al. All rights reserved. Different Cardiac Anomalies in Mother and Son with 4q-Syndrome Mon, 31 Aug 2015 06:41:33 +0000 We report a female patient with asymptomatic cor triatriatum sinister, associated with 4q34.3 deletion. Her child, carrying the same imbalance, suffers from tetralogy of Fallot. To the best of our knowledge, this is the first reported case of cor triatriatum associated with deletion of the long arm of the chromosome 4; furthermore, the majority of patients with chromosome 4 long arm syndrome have de novo deletions and only few familial cases have been reported so far. Marcello Marcì, Angela Guarina, M. Cristina Castiglione, and Nicola Sanfilippo Copyright © 2015 Marcello Marcì et al. All rights reserved. Mild Phenotype in a Patient with a De Novo 6.3 Mb Distal Deletion at 10q26.2q26.3 Wed, 29 Jul 2015 12:21:59 +0000 We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes. George A. Tanteles, Elpiniki Nikolaou, Yiolanda Christou, Angelos Alexandrou, Paola Evangelidou, Violetta Christophidou-Anastasiadou, Carolina Sismani, and Savvas S. Papacostas Copyright © 2015 George A. Tanteles et al. All rights reserved. 12q14 Microdeletions: Additional Case Series with Confirmation of a Macrocephaly Region Wed, 22 Jul 2015 08:41:27 +0000 To date, there have been only a few reports of patients carrying a microdeletion in chromosome 12q14. These patients usually present with pre- and postnatal growth retardation, and developmental delay. Here we report on two additional patients with both genotype and phenotype differences. Similar to previously published cases, one patient has haploinsufficiency of the HMGA2 gene and shows severe short stature and developmental delay. The second patient is only one of a handful without the loss of the HMGA2 gene and shows a much better growth profile, but with absolute macrocephaly. This patient’s deletion is unique and hence defines a likely macrocephaly locus that contributes to the general phenotype characterising the 12q14 syndrome. Adrian Mc Cormack, Cynthia Sharpe, Nerine Gregersen, Warwick Smith, Ian Hayes, Alice M. George, and Donald R. Love Copyright © 2015 Adrian Mc Cormack et al. All rights reserved. Unexplained False Negative Results in Noninvasive Prenatal Testing: Two Cases Involving Trisomies 13 and 18 Sun, 07 Jun 2015 11:08:38 +0000 Noninvasive prenatal testing (NIPT) validation studies show high sensitivity and specificity for detection of trisomies 13, 18, and 21. False negative cases have rarely been reported. We describe a false negative case of trisomy 13 and another of trisomy 18 in which NIPT was commercially marketed directly to the clinician. Both cases came to our attention because a fetal anatomy scan at 20 weeks of gestation revealed multiple anomalies. Karyotyping of cultured amniocytes showed nonmosaic trisomies 13 and 18, respectively. Cytogenetic investigation of cytotrophoblast cells from multiple placental biopsies showed a low proportion of nontrisomic cells in each case, but this was considered too small for explaining the false negative NIPT result. The discordant results also could not be explained by early gestational age, elevated maternal weight, a vanishing twin, or suboptimal storage or transport of samples. The root cause of the discrepancies could, therefore, not be identified. The couples involved experienced difficulties in accepting the unexpected and late-adverse outcome of their pregnancy. We recommend that all parties involved in caring for couples who choose NIPT should collaborate to clarify false negative results in order to unravel possible biological causes and to improve the process of patient care from initial counseling to communication of the result. R. Hochstenbach, G. C. M. L. Page-Christiaens, A. C. C. van Oppen, K. D. Lichtenbelt, J. J. T. van Harssel, T. Brouwer, G. T. R. Manten, P. van Zon, M. Elferink, K. Kusters, O. Akkermans, J. K. Ploos van Amstel, and G. H. Schuring-Blom Copyright © 2015 R. Hochstenbach et al. All rights reserved. 3p14 De Novo Interstitial Microdeletion in a Patient with Intellectual Disability and Autistic Features with Language Impairment: A Comparison with Similar Cases Thu, 14 May 2015 07:59:57 +0000 To date, few cases of 3p proximal interstitial deletions have been reported and the phenotype and genotype correlation is not well understood. Here, we report a new case of a 3p proximal interstitial deletion. The patient is an 11-year-old female with speech and social interaction difficulties, learning disability, and slight facial dysmorphism, but no other major malformations. An 8 Mb de novo interstitial deletion at 3p14.2-p14.1, from position 60.461.316 to 68.515.453, was revealed by means of array comparative genomic hybridization and confirmed using quantitative reverse-transcription polymerase chain reaction assays. This region includes six genes: FEZF2, CADPS, SYNPR, ATXN7, PRICKLE, and MAGI1, that are known to have a role in neurodevelopment. These genes are located on the proximal side of the deletion. We compare our case with previously well-defined patients reported in the literature and databases. Ana Belén de la Hoz, Hiart Maortua, Ainhoa García-Rives, María Jesús Martínez-González, Maitane Ezquerra, and María-Isabel Tejada Copyright © 2015 Ana Belén de la Hoz et al. All rights reserved. PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication Thu, 07 May 2015 12:25:49 +0000 The proximal region of the long arm of chromosome 15q11.2-q13 is associated with various neurodevelopmental disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes, autism, and other developmental abnormalities resulting from deletions and duplications. In addition, this region encompasses imprinted genes that cause PWS or AS, depending on the parent-of-origin. This imprinting allows for diagnosis of PWS or AS based on methylation status using methylation sensitive (MS) multiplex ligation dependent probe amplification (MLPA). Maternally derived microduplications at 15q11.2-q13 have been associated with autism and other neuropsychiatric disorders. Multiple methods have been used to determine the parent-of-origin for 15q11.2-q13 microdeletions and microduplications. In the present study, a four-year-old nondysmorphic female patient with developmental delay was found to have a de novo ~5 Mb duplication within 15q11.2 by oligonucleotide genomic array. In order to determine the significance of this microduplication to the clinical phenotype, the parent-of-origin needed to be identified. The PWS/AS MS-MLPA assay is generally used to distinguish between deletion and uniparental disomy (UPD) of 15q11.2-q13, resulting in either PWS or AS. However, our study shows that PWS/AS MS-MLPA can also efficiently distinguish the parental origin of duplications of 15q11.2-q13. Angelika J. Dawson, Janice Cox, Karine Hovanes, and Elizabeth Spriggs Copyright © 2015 Angelika J. Dawson et al. All rights reserved. Identification of Novel Mutations in Spatacsin and Apolipoprotein B Genes in a Patient with Spastic Paraplegia and Hypobetalipoproteinemia Thu, 07 May 2015 09:56:51 +0000 Complicated hereditary spastic paraplegia (HSP) presents with complex neurological and nonneurological manifestations. We report a patient with autosomal recessive (AR) HSP in whom laboratory investigations revealed hypobetalipoproteinemia raising the possibility of a shared pathophysiology of these clinical features. A lipid profile of his parents disclosed a normal maternal lipid profile. However, the paternal lipid profile was similar to that of the patient suggesting autosomal dominant transmission of this trait. Whole exome sequence analysis was performed and novel mutations were detected in both the SPG11 and the APOB genes. Genetic testing of the parents showed that both APOB variants were inherited from the father while the SPG11 variants were inherited one from each parent. Our results indicate that, in this patient, the hypobetalipoproteinemia and spastic paraplegia are unrelated resulting from mutations in two independent genes. This clinical study provides support for the use of whole exome sequencing as a diagnostic tool for identification of mutations in conditions with complex presentations. Leema Reddy Peddareddygari and Raji P. Grewal Copyright © 2015 Leema Reddy Peddareddygari and Raji P. Grewal. All rights reserved. Cognitive, Affective Problems and Renal Cross Ectopy in a Patient with 48,XXYY/47,XYY Syndrome Tue, 05 May 2015 08:01:44 +0000 Klinefelter syndrome is the most common sex chromosome abnormality (SCA) in infertile patients and 47,XXY genomic configuration constitutes most of the cases. However, additional Xs and/or Y such as 48,XXYY, 48,XXXY, and 47,XYY can occur less frequently than 47,XXY. Those configurations were considered as variants of Klinefelter syndrome. In this report, we present an infertile man with tall stature and decreased testicular volume. Semen analysis and hormonal evaluation supported the diagnosis of nonobstructive azoospermia. Genetic investigation demonstrated an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY(17)/47,XYY (13). Additionally, the patient expressed cognitive and affective problems which were documented by psychomotor retardation and borderline intelligence measured by an IQ value between 70 and 80. Systemic evaluation also revealed cross ectopy and malrotation of the right kidney in the patient. The couple was referred to microtesticular sperm extraction (micro-TESE)/intracytoplasmic sperm injection (ICSI) cycles and preimplantation genetic diagnosis (PGD). To the best of our knowledge, this is the first report of combination of XYY and XXYY syndromes associated with cognitive, affective dysfunction and renal malrotation. Sefa Resim, Faruk Kucukdurmaz, Nazım Kankılıc, Ozlem Altunoren, Erkan Efe, and Can Benlioglu Copyright © 2015 Sefa Resim et al. All rights reserved. Identification of SLC22A5 Gene Mutation in a Family with Carnitine Uptake Defect Tue, 05 May 2015 06:36:29 +0000 Primary systemic carnitine deficiency is caused by homozygous or compound heterozygous mutation in the SLC22A5 gene on chromosome 5q31. The most common presentations are in infancy and early childhood with either metabolic decompensation or cardiac and myopathic manifestations. We report a case of 9-year-old boy with dysmorphic appearance and hypertrophic cardiomyopathy. Tandem MS spectrometry analysis was compatible with carnitine uptake defect (CUD). His sister had died due to sudden infant death at 19 months. His second 4-year-old sister’s echocardiographic examination revealed hypertrophic cardiomyopathy, also suffering from easy fatigability. Her tandem MS spectrometry analyses resulted in CUD. We sequenced all the exons of the SLC22A5 gene encoding the high affinity carnitine transporter OCTN2 in the DNA. And one new mutation (c.1427T>G → p.Leu476Arg) was found in the boy and his sister in homozygous form, leading to the synthesis of an altered protein which causes CUD. The parent’s molecular diagnosis supported the carrier status. In order to explore the genetic background of the patient’s dysmorphic appearance, an array-CGH analysis was performed that revealed nine copy number variations only. Here we report a novel SLC22A5 mutation with the novel hallmark of its association with dysmorphologic feature. Hatice Mutlu-Albayrak, Judit Bene, Mehmet Burhan Oflaz, Tijen Tanyalçın, Hüseyin Çaksen, and Bela Melegh Copyright © 2015 Hatice Mutlu-Albayrak et al. All rights reserved. Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome Sun, 03 May 2015 12:19:44 +0000 This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome. Kristen Dilzell, Diana Darcy, John Sum, and Robert Wallerstein Copyright © 2015 Kristen Dilzell et al. All rights reserved. Ellis-van Creveld Syndrome: Mutations Uncovered in Lebanese Families Thu, 30 Apr 2015 11:57:41 +0000 Background. Ellis-van Creveld (EvC) syndrome is a rare, autosomal recessive disorder characterized by short stature, short limbs, growth retardation, polydactyly, and ectodermal defects with cardiac anomalies occurring in around 60% of cases. EVC syndrome has been linked to mutations in EVC and EVC2 genes. Case Presentation. We report EvC syndrome in two unrelated Lebanese families both having homozygous mutations in the EVC2 gene, c.2653C>T (p.(Arg885*)) and c.2012_2015del (p.(Leu671*)) in exons 15 and 13, respectively, with the latter being reported for the first time. Conclusion. Although EvC has been largely described in the medical literature, clinical features of this syndrome vary. While more research is required to explore other genes involved in EvC, early diagnosis and therapeutic care are important to achieve a better quality of life. Maria Valencia, Lara Tabet, Nadine Yazbeck, Alia Araj, Victor L. Ruiz-Perez, Khalil Charaffedine, Farah Fares, Rebecca Badra, and Chantal Farra Copyright © 2015 Maria Valencia et al. All rights reserved. Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis Wed, 01 Apr 2015 06:03:41 +0000 Cystic fibrosis (CF; OMIM number 219700) is an autosomal recessive disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency, chronic endobronchial infection, and male infertility. We report the case of a 47-year-old apparently normal male resulting in homozygosity for the mutation p.M348K from nonconsanguineous parents. The proband was screened using a standard panel of 70 different tested on NanoChip 400 platform. The massive parallel pyrosequencing on 454 JS machine allowed the second level analysis. The patient was firstly screened with two different platforms available in our laboratory, obtaining an ambiguous signal for the p.R347P mutation. For this reason we decided to clarify the discordant result of CFTR status by Next Generation Sequencing (NGS) using 454 Junior instrument. The patient is resulted no carrier of the p.R347P mutation, but NGS highlighted a homozygous substitution from T>A at position 1043 in the coding region, causing an amino acid substitution from methionine to lysine (p.M348K). Casual finding of p.M348K homozygote mutation in an individual, without any feature of classical or nonclassical CF form, allowed us to confirm that p.M348K is a benign rare polymorphism. Rossana Molinario, Sara Palumbo, Paola Concolino, Sandro Rocchetti, Roberta Rizza, Giovanni Luca Scaglione, Angelo Minucci, and Ettore Capoluongo Copyright © 2015 Rossana Molinario et al. All rights reserved. Case of 7p22.1 Microduplication Detected by Whole Genome Microarray (REVEAL) in Workup of Child Diagnosed with Autism Sun, 29 Mar 2015 09:55:34 +0000 Introduction. More than 60 cases of 7p22 duplications and deletions have been reported with over 16 of them occurring without concomitant chromosomal abnormalities. Patient and Methods. We report a 29-month-old male diagnosed with autism. Whole genome chromosome SNP microarray (REVEAL) demonstrated a 1.3 Mb interstitial duplication of 7p22.1 ->p22.1 arr 7p22.1 (5,436,367–6,762,394), the second smallest interstitial 7p duplication reported to date. This interval included 14 OMIM annotated genes (FBXL18, ACTB, FSCN1, RNF216, OCM, EIF2AK1, AIMP2, PMS2, CYTH3, RAC1, DAGLB, KDELR2, GRID2IP, and ZNF12). Results. Our patient presented features similar to previously reported cases with 7p22 duplication, including brachycephaly, prominent ears, cryptorchidism, speech delay, poor eye contact, and outburst of aggressive behavior with autism-like features. Among the genes located in the duplicated segment, ACTB gene has been proposed as a candidate gene for the alteration of craniofacial development. Overexpression of RNF216L has been linked to autism. FSCN1 may play a role in neurodevelopmental disease. Conclusion. Characterization of a possible 7p22.1 Duplication Syndrome has yet to be made. Recognition of the clinical spectrum in patients with a smaller duplication of 7p should prove valuable for determining the minimal critical region, helping delineate a better prediction of outcome and genetic counseling Veronica Goitia, Marcial Oquendo, and Robert Stratton Copyright © 2015 Veronica Goitia et al. All rights reserved.