Case Reports in Genetics The latest articles from Hindawi © 2018 , Hindawi Limited . All rights reserved. A Novel Mutation in ACTG2 Gene in Mother with Chronic Intestinal Pseudoobstruction and Fetus with Megacystis Microcolon Intestinal Hypoperistalsis Syndrome Thu, 14 Dec 2017 07:11:35 +0000 Background. A novel mutation in the ACTG2 gene is described in a pregnant patient followed up for chronic intestinal pseudoobstruction (CIPO) during pregnancy and her fetus with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS). Case. 24-year-old gravida 1 para 1 with CIPO and persistent nausea and vomiting in pregnancy, admitted at 28 weeks of gestation. Ultrasound revealed a fetus measuring greater than the 95th percentile, polyhydramnios, and megacystis. At delivery, the newborn was noted to have an enlarged bladder, microcolon, and intolerance of oral intake. Genetic testing of mother and child revealed a novel mutation in the ACTG2 gene (C632F>A, p.R211Q). Conclusion. This is the first case in the literature describing a novel mutation in ACTG2 associated with visceral myopathy affecting both mother and fetus/neonate. Visceral myopathy should be included in the differential diagnosis of megacystis diagnosed by ultrasound, and suspicion should increase with family history of CIPO or MMIHS. Julie R. Whittington, Aaron T. Poole, Eryn H. Dutta, and Mary B. Munn Copyright © 2017 Julie R. Whittington et al. All rights reserved. Schinzel-Giedion Syndrome with Congenital Megacalycosis in a Turkish Patient: Report of SETBP1 Mutation and Literature Review of the Clinical Features Sun, 03 Dec 2017 07:33:04 +0000 Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant disorder that results in facial dysmorphism, multiple congenital anomalies, and an increased risk of malignancy. Recently, using exome sequencing, de novo heterozygous mutations in the SETBP1 gene have been identified in patients with SGS. Most affected individuals do not survive after childhood because of the severity of this disorder. Here, we report SETBP1 mutation confirmed by molecular analysis in a case of SGS with congenital megacalycosis. Ozgul Bulut, Zeynep Ince, Umut Altunoglu, Sukran Yildirim, and Asuman Coban Copyright © 2017 Ozgul Bulut et al. All rights reserved. Novel Splicing Mutation in B3GAT3 Associated with Short Stature, GH Deficiency, Hypoglycaemia, Developmental Delay, and Multiple Congenital Anomalies Tue, 28 Nov 2017 00:00:00 +0000 B3GAT3, encoding β-1,3-glucuronyltransferase 3, has an important role in proteoglycan biosynthesis. Homozygous B3GAT3 mutations have been associated with short stature, skeletal deformities, and congenital heart defects. We describe for the first time a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, recurrent ketotic hypoglycaemia, facial dysmorphism, and congenital heart defects. A female infant, born at 34 weeks’ gestation to nonconsanguineous Caucasian parents with a birth weight of 1.9 kg, was noted to have cloacal abnormality, ventricular septal defect, pulmonary stenosis, and congenital sensorineural deafness. At 4 years of age, she was diagnosed with GH deficiency due to her short stature (height < 2.5 SD). MRI of the pituitary gland revealed a small anterior pituitary. She has multiple dysmorphic features: anteverted nares, small upturned nose, hypertelorism, slight frontal bossing, short proximal bones, hypermobile joints, and downslanting palpebral fissures. Whole exome sequencing (WES) was performed on the genomic DNA from the patient and biological mother. A heterozygous mutation in B3GAT3 (c.888+262T>G) in the invariant “GT” splice donor site was identified. This variant is considered to be pathogenic as it decreases the splicing efficiency in the mRNA. Samuel Bloor, Dinesh Giri, Mohammed Didi, and Senthil Senniappan Copyright © 2017 Samuel Bloor et al. All rights reserved. SOX5-Null Heterozygous Mutation in a Family with Adult-Onset Hyperkinesia and Behavioral Abnormalities Sun, 29 Oct 2017 10:06:16 +0000 SOX5 encodes a conserved transcription factor implicated in cell-fate decisions of the neural lineage. SOX5 haploinsufficiency induced by larger genomic deletions has been linked to a recognizable pediatric syndrome combining developmental delay with intellectual disability, mild dysmorphism, inadequate behavior, and variable additional features including motor disturbances. In contrast to SOX5-involving deletions, examples of pathogenic SOX5 small coding variations are sparse in the literature and have been described only in singular cases with phenotypic abnormalities akin to those seen in the SOX5 microdeletion syndrome. Here a novel SOX5 loss-of-function point mutation, c.13C>T (p.Arg5X), is reported, identified in the course of exome sequencing applied to the diagnosis of an unexplained adult-onset motor disorder. Aged 43 years, our female index patient demonstrated abrupt onset of mixed generalized hyperkinesia, with dystonic and choreiform movements being the most salient features. The movement disorder was accompanied by behavioral problems such as anxiety and mood instability. The mutation was found to be inherited to the patient’s son who manifested abnormal behavior including diminished social functioning, paranoid ideation, and anxiety since adolescence. Our results expand the compendium of SOX5 damaging single-nucleotide variation mutations and suggest that SOX5 haploinsufficiency might not be restrictively associated with childhood-onset syndromic disease. Michael Zech, Katharina Poustka, Sylvia Boesch, Riccardo Berutti, Tim M. Strom, Wolfgang Grisold, Werner Poewe, and Juliane Winkelmann Copyright © 2017 Michael Zech et al. All rights reserved. Palpitations and Asthenia Associated with Venlafaxine in a CYP2D6 Poor Metabolizer and CYP2C19 Intermediate Metabolizer Mon, 16 Oct 2017 00:00:00 +0000 Cardiotoxicity has been extensively reported in venlafaxine (VEN) overdoses. Asthenia is also among the common side effects described for this antidepressant. VEN is metabolized mainly by CYP2D6 and to a minor extent by CYP2C19 to the major active metabolite O-desmethylvenlafaxine (ODV). Altered pharmacokinetic parameters in patients with polymorphisms in the CYP2D6 and CYP2C19 genes that result in decreased enzymatic activity have been documented. Here we describe a patient case of VEN associated palpitations and asthenia. The patient takes VEN extended release 150 mg twice daily. Genotyping confirmed the patient is a poor metabolizer for CYP2D6 and an intermediate metabolizer for CYP2C19. We propose that the palpitations and asthenia are related to sustained VEN exposure due to reduced metabolism. Sofia Garcia, Michael Schuh, Anvir Cheema, Herjot Atwal, and Paldeep S. Atwal Copyright © 2017 Sofia Garcia et al. All rights reserved. Methylmalonic Acidemia with Novel MUT Gene Mutations Thu, 12 Oct 2017 00:00:00 +0000 A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations. Inusha Panigrahi, Savita Bhunwal, Harish Varma, and Simranjeet Singh Copyright © 2017 Inusha Panigrahi et al. All rights reserved. A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation Tue, 29 Aug 2017 06:38:50 +0000 Nicolaides-Baraitser syndrome (NCBRS) is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype. Ana Isabel Sánchez and Jorge Armando Rojas Copyright © 2017 Ana Isabel Sánchez and Jorge Armando Rojas. All rights reserved. FOXE1 Mutation Screening in a Case with Cleft Lip, Hypothyroidism, and Thyroid Carcinoma: A New Syndrome? Sun, 27 Aug 2017 08:36:59 +0000 A 26-year-old woman is referred to the Internal Medicine consultation due to increases in laboratory studies associated with Papillary Thyroid Carcinoma (PTC) that was confirmed by histopathological studies. Her clinical history revealed that, at 3 months of age, she was successfully treated with surgery for cleft lip (CL) and at the age of 24 years was diagnosed with hypothyroidism. Single nucleotide polymorphisms (SNPs) in FOXE1 and its promoter regions have been associated with various etiologies related to the thyroid, including orofacial clefting, specially cleft palate (CP) and CL, hypothyroidism (HT), and thyroid cancer. The association of CL, HT, and PTC might be component of a new syndrome; however FOXE1 coding region, which has been involved with these entities, has not exhibited mutations or SNPs. Further study of other genes may help in better characterization of the possible syndrome. Hugo Mendieta-Zerón, Angélica Jiménez-Rosales, Carlos Jhovani Pérez-Amado, and Silvia Jiménez-Morales Copyright © 2017 Hugo Mendieta-Zerón et al. All rights reserved. Neurological Manifestations of X-Linked Ichthyosis: Case Report and Review of the Literature Sun, 13 Aug 2017 07:00:04 +0000 A 5-year-old boy presented with mild autism and attention-deficit hyperactivity disorder (ADHD). Chromosomal microarray demonstrated a 1.7 Mb deletion at Xp22.31, which was consistent with X-linked ichthyosis (XLI). Further exam revealed dry, scaly skin on his abdomen and pretibial areas. Patients with mutations involving solely the STS gene or the recurrent ~2 Mb deletion may present with ADHD, whereas those with larger deletions including the NLGN4 gene can present with both ADHD and autism. However, our patient presented with mild autism in addition to ADHD despite having only the recurrent deletion without loss of NLGN4. Such neurological manifestations of XLI warrant attention as practical targets of clinical management. William S. Baek and Umut Aypar Copyright © 2017 William S. Baek and Umut Aypar. All rights reserved. What Drives Embryo Development? Chromosomal Normality or Mitochondria? Tue, 08 Aug 2017 07:52:52 +0000 Objective. To report the arrest of euploid embryos with high mtDNA content. Design. A report of 2 cases. Setting. Private fertility clinic. Patients. 2 patients, 45 and 40 years old undergoing IVF treatment. Interventions. Mature oocytes were collected and vitrified from two ovarian stimulations. Postthaw, survived mature oocytes underwent fertilization by intracytoplasmic sperm injection (ICSI). Preimplantation genetic screening (PGS) and mitochondrial DNA (mtDNA) copy number were done using next generation sequencing (NGS). The only normal embryo among the all-biopsied embryos had the highest “Mitoscore” value and was the only arrested embryo in both cases. Therefore, the embryo transfer was cancelled. Main Outcome Measures. Postthaw survival and fertilization rate, embryo euploidy, mtDNA copy number, and embryo development. Results. In both patients, after PGS only 1 embryo was euploid. Both embryos had the highest mtDNA copy number from all tested embryos and both embryos were arrested on further development. Conclusions. These cases clearly demonstrate the lack of correlation between mtDNA value (Mitoscore) and chromosomal status of embryo. A. Bayram, I. Elkhatib, A. Arnanz, A. Linan, F. Ruiz, B. Lawrenz, and H. M. Fatemi Copyright © 2017 A. Bayram et al. All rights reserved. An Interstitial 4q Deletion with a Mosaic Complementary Ring Chromosome in a Child with Dysmorphism, Linear Skin Pigmentation, and Hepatomegaly Thu, 27 Jul 2017 00:00:00 +0000 Interstitial deletions of 4q are rarely reported, vary in size, and have limited genotype-phenotype correlations. Here, genome-wide array CGH analysis identified a 21.6 Mb region of copy number loss at 4q12-q21.1 in a patient diagnosed with dysmorphism, linear skin pigmentation, and hepatomegaly. An additional small ring chromosome was detected in 5/30 cells examined via G-banding. Confirmation of the origin of the ring chromosome was obtained by FISH analysis which identified that the ring chromosome contained material from the deleted region of chromosome 4 and was therefore complementary to the 21.6 Mb deletion. Further microarray studies in the proband using a different microarray platform showed no evidence of mosaicism. This case highlights the importance of an integrated approach to cytogenetic analysis and demonstrates the value of G-banding for detecting mosaicism, as current microarray platforms are unable to detect low level mosaics. J. Carter, H. Brittain, D. Morrogh, N. Lench, and J. J. Waters Copyright © 2017 J. Carter et al. All rights reserved. Freeman–Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa Thu, 11 May 2017 07:05:14 +0000 We report a case of a male baby who has characteristic signs of Freeman–Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman–Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman–Sheldon syndrome in sub-Saharan Africa. A. M. Ali, R. M. Mbwasi, G. Kinabo, E.-J. Kamsteeg, B. C. Hamel, and M. C. J. Dekker Copyright © 2017 A. M. Ali et al. All rights reserved. Neoplasia in Cri du Chat Syndrome from Italian and German Databases Mon, 24 Apr 2017 09:58:24 +0000 Cri du Chat syndrome (CdC) is a chromosomal abnormality (deletion of short arm of chromosome 5) associated with intellectual disability and typical anatomical abnormalities. Research up to now focuses on the management of the disease during childhood. The longer lifespan of these patients warrants deeper investigations of how and if aging could be affected by the syndrome. We decided to focus on the association of the disease with proliferative disorders. Data on proliferative disorders in a cohort of 321 patients from Italian and German Cri du Chat databases were collected. A neoplasia was present in four patients (age 10–50 yrs), and a fifth patient developed a cholesteatoma during childhood. It is of interest that two cases had an early onset of the neoplasia as compared to the expected age of development in the general population. The chromosome region deleted in 5p does not contain genes whose haploinsufficiency is a well-known main cause of the proliferative disorders observed. We nonetheless believe that reporting even sporadic cases of proliferative disorders in CdC patients may increase our knowledge as to the natural history of the disease. In conclusion, available information suggests that surveillance for cancer development in CdC can follow the guidelines for the general population. Andrea Guala, Marianna Spunton, Silvia Kalantari, Ingo Kennerknecht, and Cesare Danesino Copyright © 2017 Andrea Guala et al. All rights reserved. Pathogenic Variant in ACTB, p.Arg183Trp, Causes Juvenile-Onset Dystonia, Hearing Loss, and Developmental Delay without Midline Malformation Wed, 12 Apr 2017 09:24:24 +0000 ACTB encodes the β-actin, and pathogenic variations in this gene have typically been associated with Baraitser-Winter cerebrofrontofacial syndrome, a congenital malformation syndrome characterized by short stature, craniofacial anomalies, and cerebral anomalies. Here, we describe the third case with the p.Arg183Trp variant in ACTB causing juvenile-onset dystonia. Our patient has severe, intractable dystonia, developmental delay, and sensorineural hearing loss, besides hyperintensities in the caudate nuclei and putamen on the brain MRI, which is a distinct but overlapping phenotype with the previously reported case of identical twins with the same alteration in ACTB. Erin Conboy, Filippo Vairo, Darrel Waggoner, Carole Ober, Soma Das, Radhika Dhamija, Eric W. Klee, and Pavel Pichurin Copyright © 2017 Erin Conboy et al. All rights reserved. Respiratory Failure due to Severe Obesity and Kyphoscoliosis in a 24-Year-Old Male with Molecularly Confirmed Prader-Willi Syndrome in Tertiary Hospital in Northern Tanzania Sun, 09 Apr 2017 00:00:00 +0000 Obesity, mild intellectual disability, hypotonia, poor sucking, cryptorchidism in males, hypogonadism, and kyphoscoliosis are common features of Prader-Willi syndrome (PWS). We report a case who had severe respiratory complications due to extreme obesity and kyphoscoliosis, which are important causes of morbidity and mortality, and discuss management. Furthermore, this is the first molecularly confirmed PWS case in Sub-Saharan Africa outside South Africa. Elichilia R. Shao, Lucas F. Kiyegi, Amos O. Mwasamwaja, Kajiru Kilonzo, and Ben C. J. Hamel Copyright © 2017 Elichilia R. Shao et al. All rights reserved. Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly Wed, 29 Mar 2017 06:58:47 +0000 Interstitial 17q24.1 or 17q24.2 deletions were reported after conventional cytogenetic analysis or chromosomal microarray analysis in patients presenting intellectual disability, facial dysmorphism, and/or malformations. We report on a fetus with craniofacial dysmorphism, talipes equinovarus, and syndactyly associated with a de novo 2.5 Mb 17q24.1q24.2 deletion. Among the deleted genes, KPNA2 and PSMD12 are discussed for the correlation with the fetal phenotype. This is the first case of prenatal diagnosis of 17q24.1q24.2 deletion. Marie-Emmanuelle Naud, Lucie Tosca, Jelena Martinovic, Julien Saada, Corinne Métay, Loïc Drévillon, Virginie Benoit, Sophie Brisset, and Gérard Tachdjian Copyright © 2017 Marie-Emmanuelle Naud et al. All rights reserved. Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome Tue, 14 Mar 2017 00:00:00 +0000 Congenital nephrotic syndrome, a rare and severe disease, is inherited as an autosomal recessive trait. The disease manifests shortly after birth and occurs predominantly in families of Finnish origin but has now been observed in all countries and races. Mutations in the NPHS1 gene, which encodes nephrin, are the main causes of congenital nephrotic syndrome in patients. In this study, we report the first mutational analysis of the NPHS1 gene in three unrelated children from three different Vietnamese families. These patients were examined and determined to be suffering from congenital nephrotic syndrome in the Department of Pediatrics, Vietnam National Hospital of Pediatrics. All 29 exons and exon-intron boundaries of NPHS1 were analyzed by PCR and DNA sequencing. Genetic analysis of the NPHS1 gene revealed one compound heterozygous variant p.Glu117Lys, one heterozygous missense mutation p.Asp310Asn, and one heterozygous frame-shifting mutation (c.3250_3251insG causing p.Val1084Glyfs12) in patient 1. In patient 2, one heterozygous variant p.Glu117Lys and one novel heterozygous missense mutation p.Ser324Ala were identified. Finally, a novel missense mutation p.Arg802Leu and a novel nonsense mutation (c.2442C>G causing p.K792) were identified in patient 3. Thi Kim Lien Nguyen, Van Dem Pham, Thu Huong Nguyen, Trung Kien Pham, Thi Quynh Huong Nguyen, and Huy Hoang Nguyen Copyright © 2017 Thi Kim Lien Nguyen et al. All rights reserved. Goldenhar Syndrome with Dextrocardia and Right Pulmonary Hypoplasia: An Unusual Association Thu, 09 Mar 2017 08:13:47 +0000 Goldenhar syndrome (GS), a rare condition, occurring due to defect in development of first and second branchial arches, is characterized by a combination of various anomalies involving face, eyes, ears, vertebrae, heart, and lungs. The etiology of GS is not fully known, although various hypotheses have been proposed along with its genetic association and many other causes. Facial asymmetry and hypoplasia of the mandible are characteristic features of GS along with microtia and preauricular appendages and pits. Dextrocardia or pulmonary hypoplasia in GS has previously been reported separately. We report a 7-year-old female child of GS with combination of anomalies, dextrocardia, and pulmonary hypoplasia, which is a rare association. Nagendra Chaudhary, Sandeep Shrestha, and Hemant Kumar Halwai Copyright © 2017 Nagendra Chaudhary et al. All rights reserved. Urea Cycle Defects: Early-Onset Disease Associated with A208T Mutation in OTC Gene—Expanding the Clinical Phenotype Sun, 05 Feb 2017 07:40:42 +0000 Ornithine transcarbamylase deficiency (OMIM: 311250) is the most common disorder of urea cycle disorders, accounting for nearly 50% of all cases. We report a case of a two-month- old male patient, who attends our medical genetics consultation because of low citrulline levels and elevated glutamine to citrulline ratio detected by expanded newborn screening with tandem mass spectrometry. He is an asymptomatic male with a normal physical examination and appropriate neurodevelopmental milestones. The patient has a family history of one older brother who died at 18 months old from severe and sudden hyperammonemia and a maternal aunt who suddenly died at two years old. He had high plasma ammonium concentration and a confirmed OTC mutation (p.A208T). Usually, this mutation causes OTC deficiency of late onset in adult males. However, this report raises awareness about mutations previously described as a late-onset causing disease, which can cause severe hyperammonemia and high risk of dying at an early age. Ana Isabel Sánchez, Alejandra Rincón, Mary García, and Fernando Suárez-Obando Copyright © 2017 Ana Isabel Sánchez et al. All rights reserved. A Newborn with Panhypopituitarism and Seizures Wed, 01 Feb 2017 09:51:23 +0000 Interstitial deletions on the short arm of chromosome 20 are uncommon, and therefore the clinical phenotype is poorly defined. Very few cases have been reported in the literature so far. In this report, we describe a 4-month-old female with a heterozygous deletion at 20p11.21p12.1 with panhypopituitarism and cardiac, gastrointestinal, and genitourinary anomalies along with dysmorphic facial features. We compared and discussed similar cases with overlapping deletions in 20p11 region. We wish to report this rare occurrence as this may better define the phenotypes of the 20p interstitial deletion with certain dysmorphic features, multiorgan involvement, and related clinical characteristics in this patient population. Trupti Kale, Rachit Patil, and Ramesh Pandit Copyright © 2017 Trupti Kale et al. All rights reserved. Costello Syndrome and Umbilical Ligament Rhabdomyosarcoma in Two Pediatric Patients: Case Reports and Review of the Literature Thu, 19 Jan 2017 00:00:00 +0000 Costello syndrome is caused by heterozygous de novo missense mutations in the protooncogene HRAS with tumor predisposition, especially rhabdomyosarcoma. We here report two pediatric patients with Costello syndrome and umbilical ligament rhabdomyosarcoma. A review of the literature published in English in MEDLINE from January 1971 to June 2016 using the search terms “Costello syndrome” and “rhabdomyosarcoma” was performed, including two new cases that we describe. Twenty-six patients with Costello syndrome and rhabdomyosarcoma were recorded with mean age of diagnosis of 2 years and 8 months. The most common tumor location was the abdomen/pelvis, including four out of ten of those in the umbilical ligament. The most common histological subtype was embryonal rhabdomyosarcoma. Overall survival was 43%. A total of 17 rhabdomyosarcomas in pediatric patients arising in the umbilical ligament were recorded with mean age of diagnosis of 3 years and 4 months. Overall survival was 69%. Costello syndrome is a poorly known disorder in pediatric oncology but their predisposition to malignancies implies the need for a new perspective on early diagnosis and aggressive medical and surgical treatment. Carlos Sánchez-Montenegro, Alejandra Vilanova-Sánchez, Saturnino Barrena-Delfa, Jair Tenorio, Fernando Santos-Simarro, Sixto García-Miñaur, Pablo Lapunzina, and Leopoldo Martínez-Martínez Copyright © 2017 Carlos Sánchez-Montenegro et al. All rights reserved. Novel Pathogenic Variant in TGFBR2 Confirmed by Molecular Modeling Is a Rare Cause of Loeys-Dietz Syndrome Mon, 09 Jan 2017 14:31:41 +0000 Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular findings of aneurysm and/or dissection of cerebral, thoracic, or abdominal arteries and skeletal findings. We report a case of a novel pathogenic variant in TGFBR2 and phenotype consistent with classic LDS. The proband was a 10-year-old presenting to the genetics clinic with an enlarged aortic root (Z-scores 5-6), pectus excavatum, and congenital contractures of the right 2nd and 3rd digit. Molecular testing of TGFBR2 was sent to a commercial laboratory and demonstrated a novel, likely pathogenic, variant in exon 4, c.1061T>C, p.(L354P). Molecular modeling reveals alteration of local protein structure as a result of this pathogenic variant. This pathogenic variant has not been previously reported in LDS and thus expands the pathogenic variant spectrum of this condition. Michael T. Zimmermann, Raul A. Urrutia, Patrick R. Blackburn, Margot A. Cousin, Nicole J. Boczek, Eric W. Klee, Colleen Macmurdo, and Paldeep S. Atwal Copyright © 2017 Michael T. Zimmermann et al. All rights reserved. Further Evidence That the CFTR Variant c.2620-6T>C Is Benign Mon, 09 Jan 2017 06:26:41 +0000 The c.2620-6T>C variant in the CFTR gene is a rare variant about which little is known. We present an asymptomatic adult who has this variant as well as the well described delta F508 pathogenic variant in transpresentation. This patient provides additional evidence that this is a benign polymorphism. Violet I. Wallerstein and Robert Wallerstein Copyright © 2017 Violet I. Wallerstein and Robert Wallerstein. All rights reserved. Familial Case of Pelizaeus-Merzbacher Disorder Detected by Oligoarray Comparative Genomic Hybridization: Genotype-to-Phenotype Diagnosis Wed, 04 Jan 2017 07:00:24 +0000 Introduction. Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. It is caused by mutation in the PLP1 gene. Case Description. We report a 9-year-old boy referred for oligoarray comparative genomic hybridization (OA-CGH) because of intellectual delay, seizures, microcephaly, nystagmus, and spastic paraplegia. Similar clinical findings were reported in his older brother and maternal uncle. Both parents had normal phenotypes. OA-CGH was performed and a 436 Kb duplication was detected and the diagnosis of PMD was made. The mother was carrier of this 436 Kb duplication. Conclusion. Clinical presentation has been accepted as being the mainstay of diagnosis for most conditions. However, recent developments in genetic diagnosis have shown that, in many congenital and sporadic disorders lacking specific phenotypic manifestations, a genotype-to-phenotype approach can be conclusive. In this case, a diagnosis was reached by universal genomic testing, namely, whole genomic array. Kimia Najafi, Roxana Kariminejad, Kaveh Hosseini, Azadeh Moshtagh, Gole Maryam Abbassi, Neda Sadatian, Masood Bazrgar, Ariana Kariminejad, and Mohamad Hassan Kariminejad Copyright © 2017 Kimia Najafi et al. All rights reserved. An Interstitial Deletion at 7q33-36.1 in a Patient with Intellectual Disability, Significant Language Delay, and Severe Microcephaly Thu, 08 Dec 2016 11:58:25 +0000 Interstitial deletions of the distal 7q region are considered a rare entity. In this report, we describe a seven-year-old male with a heterozygous interstitial deletion at 7q33-36.1 with characteristic dysmorphic facial features, intellectual disability, severe microcephaly, and significant language delay. The primary focus of our report is to compare our case with the few others in the literature describing interstitial deletions at the long arm of chromosome 7. Based on the various breakpoints in prior studies, a number of phenotypic variations have been identified that are unique to each of the reports. However, there are also a number of similarities among these cases as well. We hope to provide a concise review of the literature and genes involved within our deletion sequence in the hope that it will contribute to creating a phenotypic profile for this patient population. Trupti Kale and Melissa Philip Copyright © 2016 Trupti Kale and Melissa Philip. All rights reserved. Ring Chromosome 4 in a Child with Multiple Congenital Abnormalities: A Case Report and Review of the Literature Tue, 16 Aug 2016 09:16:10 +0000 A female child born preterm with intrauterine growth retardation and presenting with facial dysmorphism with clefts, microcephaly, limb deformities, and congenital abnormalities involving cardiovascular and urinary systems is described. Chromosomal analysis showed a de novo 46,XX,r(4)(p15.3q35) karyotype. The clinical features of the patient were compared with the phenotypic characteristics of 17 previously reported cases with ring chromosome 4 and those with Wolf-Hirschhorn syndrome (4p-). Clinical features observed in this case are consistent with the consensus phenotype in ring chromosome 4. Patent ductus arteriosus and bilateral talipes equinovarus observed in this baby widen the phenotypic spectrum associated with ring chromosome 4. C. S. Paththinige, N. D. Sirisena, U. G. I. U. Kariyawasam, L. P. C. Saman Kumara, and V. H. W. Dissanayake Copyright © 2016 C. S. Paththinige et al. All rights reserved. Adult Prader-Willi Syndrome: An Update on Management Wed, 08 Jun 2016 11:57:41 +0000 With the advancement of medical care, the survival of most patients with syndromal genetic disease is greatly improved. In this case report, we have reported an adult Prader-Willi syndrome patient who is being diagnosed at the age of 33. The clinical features and their associated complications during adulthood have been reviewed. Luk Ho-Ming Copyright © 2016 Luk Ho-Ming. 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.