Journal of Pediatric Genetics - Volume 1, issue 2

Authors: Faith, Myles S.

Article Type: Other

DOI: 10.3233/PGE-2012-013

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 69-70, 2012

Authors: Gabbett, Michael T.

Article Type: Review Article

Abstract: The oculoauriculovertebral spectrum (OAVS) is a well-described pattern of congenital malformations primarily characterized by hemifacial microsomia and/or auricular dysplasia. However, the birth prevalence of OAVS is poorly characterized. Figures ranging from 1 in 150,000 through to 1 in 5,600 can be found in the literature – the latter figure being the most frequently quoted. This study aims to evaluate the reasons behind such discrepant figures and to refine the estimated birth prevalence of OAVS. Published reports on the incidence and prevalence of OAVS were systematically sought after. This evidence was critically reviewed. Data from appropriate studies was amalgamated to refine …the estimate of the birth prevalence for OAVS. Two main reasons were identified why birth prevalence figures for OAVS are so highly discrepant: differing methods of case ascertainment and the lack of a formal definition for OAVS. This study refines the estimate of birth prevalence for OAVS to between 1 in 40,000 and 1 in 30,000. This number needs to be confirmed in a large well-designed prospective study using a formally agreed-upon definition for OAVS. Show more

Keywords: Incidence, prevalence, oculoauriculovertebral, syndrome, Goldenhar syndrome

DOI: 10.3233/PGE-2012-014

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 71-77, 2012

Authors: Shastry, Barkur S.

Article Type: Review Article

Abstract: Individual variation in drug response and adverse drug reactions (ADRs) are a serious problem in medicine. This individual variation in drug response could be due to multiple factors but there is strong evidence that genetic factors play a significant role in drug response variability and toxicity. Although substantial studies that link genetic variants to inter-individual difference in drug response in adults have been reported, such studies are comparatively rare in pediatric medicine. The ultimate goal of medical research is to improve human health in every disease and every patient. Many diseases such as asthma, autism, epilepsy, juvenile rheumatoid arthritis and …attention-deficit hyperactivity disorder develop during childhood. Human development is a rapidly changing process. In children, there are differences in absorption, distribution, excretion and metabolizing capabilities of a drug compared with adults. Therefore, many pharmacological and toxicological actions of drugs in children are not predictable from adult experience. It is also possible that children may experience a different range of ADRs that may have long-term implications for their development. Therefore, an improved understanding of the drug transformation pathways for all age groups is necessary. Such studies could provide insight into the susceptibility of a child to ADRs. The availability of the complete sequence of human genome and the biochip technology may help in identifying the polymorphic variations in drug related genes. In this regard, pharmacogenetic and pharmacogenomic studies may play an important role in providing markers of increased risk or susceptibility. Based on this genetic information, children at risk can be identified before therapy is initiated and pediatric ADRs may be minimized. In this short article, an attempt has been made to emphasize the importance of pharmacogenomics in pediatrics. Show more

Keywords: Drug, genetics, medicine, pediatrics, pharmacogenetics, safety, toxicity

DOI: 10.3233/PGE-2012-015

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 79-84, 2012

Authors: Wang, Kai | Zhang, Haitao | Mentch, Frank D. | Bradfield, Jonathan P. | Glessner, Joseph T. | Qiu, Haijun | Guo, Yiran | Hou, Cuiping | Frackelton, Edward C. | Thomas, Kelly | Bender, Amber | Albano, Anthony | Otieno, George | Garris, Maria | Seidler, Kallyn | Moy, Alexander | Kim, Cecilia E. | Keating, Brendan | Chiavacci, Rosetta M. | Grundmeier, Robert | Sleiman, Patrick A. | Grant, Struan F.A. | Hakonarson, Hakon

Article Type: Research Article

Abstract: Previous large-scale genome-wide association studies in adult populations have implicated ~100 loci in determining high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, or triglyceride levels. However, whether these loci also contribute to variations of lipid traits in pediatric populations remain unknown. Here we assayed a population of Philadelphia children by high-density single nucleotide polymorphism arrays, and performed association analysis on lipid traits ascertained from lipid measurements stored in electronic medical records. We examined previously reported lipid trait associations, and found that most of them show identical direction of association in our pediatric cohorts, including genome-wide significant association on cholesteryl ester transfer …protein with HDL-C levels (rs3764261, P = 2.1 × 10−8 ) and other significant associations on oxysterol-binding protein-like protein 7, low-density lipoprotein receptor-related protein 4 and low-density lipoprotein receptor-related protein 1. Additionally, we identified suggestive association on low-density lipoprotein receptor-related protein 1B with HDL-C levels (rs17736712, P = 2.1 × 10−7 ), but this signal is not supported by previous meta-analysis on adult cohorts. Finally, we examined rare copy number variants and identified deletions encompassing tetratricopeptide repeat domain 39B in two children with extreme lipid measures. Our results highlight the commonalities and differences of genetic components in determining lipid traits in pediatric versus adult populations. Furthermore, our study demonstrates the unique utility of automated information retrieval from electronic medical records in facilitating the identification of genotype-phenotype associations. Show more

Keywords: HDL, LDL, TG, GWAS, lipid

DOI: 10.3233/PGE-2012-016

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 85-98, 2012

Authors: Patitucci, Alessandra | Magariello, Angela | Ungaro, Carmine | Muglia, Maria | Conforti, Francesca L. | Gabriele, Anna L. | Citrigno, Luigi | Sproviero, William | Mazzei, Rosalucia

Article Type: Research Article

Abstract: The routine molecular test for spinal muscular atrophy (SMA) diagnosis is based on the detection of a homozygous deletion of exons 7 and 8 of the telomeric copy of the survival motor neuron gene (SMN1 ). The presence of the centromeric copy of the SMN gene (SMN2 ) does not allow the detection of the hemizygous absence of the SMN1 gene, which characterizes the disease carriers. The demand for a quantitative SMN1 test is permanently growing because there is a high incidence of carriers. The disease is severe and to date there are no effective pharmacological treatments. …Here, we present a non-radioactive assay based on real time quantitative polymerase chain reaction. We analyzed eight SMA patients, 14 SMA relatives and 50 health individuals from Southern Italy by real time quantitative method in order to identify haploid deletion occurring in SMA carriers. SMN1 copy number was determined by the comparative threshold cycle method (ΔΔCt). The results confirmed the deletion in all homozygous patients and permitted an evaluation of the number of alleles in the healthy carriers. This method is fast, reproducible, and enables us to discriminate carriers from healthy homozygous, which is impossible with normal techniques. Show more

Keywords: SMA, SMN1, real time PCR, quantitative assay

DOI: 10.3233/PGE-2012-017

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 99-102, 2012

Authors: Morgan, Angharad R. | Thompson, John M.D. | Waldie, Karen E. | Cornforth, Christine M. | Turic, Darko | Sonuga-Barke, Edmund J.S. | Lam, Wen-Jiun | Ferguson, Lynnette R. | Mitchell, Edwin A.

Article Type: Research Article

Abstract: Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate …single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A 1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems. Show more

Keywords: SGA, ADHD, genetic association, SNP

DOI: 10.3233/PGE-2012-018

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 103-113, 2012

Authors: Hantash, Feras M. | Wang, Boris T. | Owen, Renius | Ross, Leslie P. | Mahon, Loretta W. | Boyar, Fatih Z. | Anguiano, Arturo | Strom, Charles M.

Article Type: Research Article

Abstract: In a screen of patients by fluorescence in-situ hybridization and array comparative genomic hybridization in the past two years (July 2007--July 2009), we identified two patients with duplications in the 22q11.22-23, occurring outside the common DiGeorge syndrome/valocardiofacial syndrome region. Fluorescent in-situ hybridization, multiplex ligation-dependent probe amplification and high density bacterial artificial chromosomes and oligo arrays were used to identify the extent of the duplications. In one patient the duplication extended from LCR22-E/5 to LCR22-H/8, which is similar to recently described 22q11.2 distal duplications, while in the second patient, a de novo duplication was identified extending between LCR22-E/5 to LCR22-F/6. …The second proband also harbored a de novo 15q14 duplication, complicating phenotype interpretation. The patients were affected with speech delay and autistic features, but neither reported cardiac concern or dysmorphic features. Show more

Keywords: 22q11.2, duplication, mental retardation, autism, tic behavior, speech, DiGeorge syndrome/valocardiofacial syndrome

DOI: 10.3233/PGE-2012-019

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 115-124, 2012

Authors: Flore, Leigh Anne | Leon, Eyby | Maher, Tom A. | Milunsky, Jeff M.

Article Type: Research Article

Abstract: Capillary malformation-arteriovenous malformation (CM-AVM; MIM 60354) is an autosomal dominant disorder characterized by multifocal cutaneous capillary malformations, often in association with fast-flow vascular lesions, which may be cutaneous, subcutaneous, intramuscular, intraosseus, or cerebral arteriovenous malformations or arteriovenous fistulas. CM-AVM results from heterozygous mutations in the RASA1 gene. Capillary malformations of the skin are common, and clinical examination alone may not be able to definitively diagnose-or exclude- CM-AVM. We report a family in which the proband was initially referred for a genetic evaluation in the neonatal period because of the presence of a cardiac murmur and minor dysmorphic features. Both …he and his mother were noted to have multiple capillary malformations on the face, head, and extremities. Echocardiography revealed dilated head and neck vessels and magnetic resonance imaging and angiography of the brain revealed a large infratentorial arteriovenous fistula, for which he has had two embolization procedures. RASA1 sequence analysis revealed a heterozygous mutation, confirming his diagnosis of CM-AVM. We established targeted mutation analysis for the proband's mother and sister, the latter of whom is a healthy 3-year-old whose only cutaneous finding is a facial capillary malformation. This revealed that the proband's mother is also heterozygous for the RASA1 mutation, but his sister is negative. Consequently, his mother will undergo magnetic resonance imaging and angiography screening for intracranial and spinal fast-flow lesions, while his sister will require no imaging or serial evaluations. Targeted mutation analysis has been offered to additional maternal family members. This case illustrates the benefit of molecular testing in diagnosis and making screening recommendations for families with CM-AVM. Show more

Keywords: Capillary malformation, arteriovenous malformation, RASA1, arteriovenous fistula

DOI: 10.3233/PGE-2012-020

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 125-129, 2012

Authors: Mimbacas, Adriana | Vitarella, Graciela | Souto, Jorge | Reyes, Ana Laura | Farias, Joaquina | Fernández, Mariana | Fabregat, Matias | Javiel, Gerardo

Article Type: Research Article

Abstract: The concept of a new form of diabetes, with signs of both types 1 and 2, has not been often considered, until recently. It is of immense interest to explore the role of the admixture that characterizes the Uruguayan population (higher and different from other Latin America countries) for the presence of such expression of that particular disease. We describe here a child who possibly presents with this expression. He had typical signs of both diabetic conditions: type 1 (young age, positive immunologic and genetic markers, ketoacidosis) and type 2 (obesity [body mass index = 36 kg/m2 ] and acanthosis …nigricans). In spite of complying with the established guidelines, therapeutic and nutritional control, quality of life and good metabolic control, the patient's obesity had been continually increasing. Looking for a genetic explanation, we studied three single nucleotide polymorphisms involved in three different metabolic pathways (peroxisome proliferator-activated receptor gamma 2, insulin receptor substrate-1 and uncoupling protein-2) associated with insulin resistance. Our patient showed three mutations, GG, GA, GG, associated with insulin resistance that explains obesity associated with limited response to the commonly used drugs. According to the clinical presentation and the genetic and immunological background, we considered that this patient presents with a new form of diabetes. We have termed this particular disease “hybrid diabetes” because of the involvement of genes associated with both the classical type of diabetes. However, at least in an admixed population such as in Uruguay, clinical classification would not strictly dictate the choice of treatment. Show more

Keywords: Type 1 diabetes, HLA, GAD antibody

DOI: 10.3233/PGE-2012-021

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 131-134, 2012

Authors: Cohen, Lilian | Samanich, Joy | Pan, Quilu | Mehta, Lakshmi | Marion, Robert

Article Type: Research Article

Abstract: Williams syndrome (WS) is a complex genomic disorder entailing distinctive facial dysmorphism, cardiovascular abnormalities, intellectual disabilities, unusual behavioral features, and a specific cognitive profile with considerable variability. Additional symptoms include endocrine abnormalities, renal anomalies and connective tissue disorders. We report a monozygotic twin patient with WS who presented with multicystic kidneys in the newborn period, and, in addition to the typical WS deletion at 7q11.23, was found to have a de novo 1.7 Mb deletion in the 17q12 region on microarray comparative genomic hybridization. The co-twin was selectively terminated at 23 wk of gestation after being diagnosed with bilateral multicystic …dysplastic kidneys and anhydramnios. Review of the literature shows that deletion of chromosome 17q12, encompassing hepatocyte nuclear factor 1beta gene, is associated with cystic renal disease and is the first recurrent genomic deletion associated with maturity onset diabetes of the young. In addition, reports of female reproductive tract malformations and patients with neurocognitive or psychiatric phenotypes have recently been described. This review of the literature summarizes 47 other cases involving 17q12 deletions with wide variability in phenotype, possibly suggesting a contiguous gene syndrome. It is likely that the additional 17q12 deletion has played a role in modifying the phenotype in our patient. This case highlights the importance of using array comparative genomic hybridization in the clinical setting to uncover the etiology of atypical findings in individuals with known microdeletion syndromes. Show more

Keywords: Williams syndrome, microarray, 17q12 deletion, hepatocyte nuclear factor 1beta gene deletion, genotype-phenotype correlation

DOI: 10.3233/PGE-2012-022

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 135-141, 2012

Authors: Eggermann, Thomas | Spengler, Sabrina | Gamerdinger, Ulrike | Denecke, Bernd | Grimm, Silke | Grimm, Manfred | Schubert, Regine | Schwanitz, Gesa

Article Type: Research Article

Abstract: In 2006, we reported the first case with a pure duplication of proximal 3q. In these rare aberrations, detailed clinical and developmental investigations at different ages are required to provide sufficient phenotypic documentation. Clinical and psychological differences were therefore regularly documented in our case. Supplemental genetic investigations comprised conventional karyotyping, fluorescence in-situ hybridization, single nucleotide polymorphism array analysis, and microsatellite typing. Thus, the exact position and extension of the duplication (3q13.11q23), the size (35.6 Mb), and the paternal origin could be determined. The development of our patient was followed up in detail over a period of 7.5 yr and thus …enabled specific characterization of the phenotype of the patient. Show more

Keywords: Duplication 3q13.11q23, de novo, longitudinal studies, phenotype specification, developmental differences

DOI: 10.3233/PGE-2012-023

Citation: Journal of Pediatric Genetics, vol. 1, no. 2, pp. 143-147, 2012