Genetics in the Third Millennium
Volume:6 Issue: 2, 2008

Wiskott-Aldrich syndrome (WAS) is a life-threatening recessive immunodeficiency disease caused by mutations of the WAS protein (WASP) gene, characterized by thrombocytopenia, eczema and recurrent infections. In order to have accurate diagnosis for the patient referred to the Children Medical Center Hospital, Department of Allergy & Clinical Immunology who were clinically diagnosed as Wiskott-Aldrich patients, genetic analysis was done by polymerase chain reaction (PCR) and sequencing method. In this study, we found two new mutations (P412fsX446 and Gly70Arg) and a previously reported mutation (Arg13X) in WAS gene, responsible for Wiskott-Aldrich syndrome.

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in 1 of 2,000 live births. The function of the suture is to permit molding at the birth canal, adjustment for the expanding brain, and absorption of mechanical trauma in childhood. Craniosynostosis results from premature ossification and fusion of the skull sutures and generally results in alteration of the shape of the cranial vault and/or premature closure of the fontanelles. When associated anomalies or delays are present, the possibility of a syndrome should be considered. There are more than 180 syndromes that manifest craniosynostosis, and significant progress has been made in understanding their clinical and molecular aspects. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and MSX2 genes cause the most common and/or well-characterized syndromes. Approximately 85% of cases are believed to be nonsyndromic with no identifiable gene mutation. Clinical evaluations should include in-depth antenatal history and documentation of any teratogenic exposure, a 3-generation family history and a comprehensive review of systems. The autosomal dominant inheritance and variable expressivity of many disorders mandates that patients and available first-degree relatives should undergo detailed clinical examination, including subtle malformations. Because of variable expressivity, the identification of a mutation in an affected individual should be followed by parental testing. In autosomal dominant types of craniosynostosis, mutation carriers have a 50% risk of passing the affected gene to their offspring. Negative parental mutation testing still leaves a small (_1%) risk of recurrence because of potential gonadal mosaicism. Truly nonsyndromic craniosynostosis is thought to be a multifactorial trait with recurrent risk around 5% for coronal and around 1% for sagittal suture fusion.

We report a 1-year-old boy with craniosynostosis, microcephaly, developmental delay and dysmorphic features. His karyotype was 46,XX,add2q. Chromosomal study of parents was normal. The imbalance on chromosome 2 in the patient was further defined using comparative genomic hybridization (CGH), which revealed a loss of material from 2q37.3→qter and a gain of 5q34→qter. Florescent in situ hybridization (FISH) studies using subtelomeric 2q and 5q were used to confirm 2q deletion and 5q duplication. It demonstrated 3 signals for 5q terminal and 1 signal for 2q terminal. FISH studies of parents were normal. Recently it has been proposed that an extra copy of the MSX2 gene that is mapped to 5q35.2 causes premature synostosis of the sutures via the MSX2-mediated pathway of calvarial osteogenic differentiation. Our case gives further support of the role of extra copy of MSX2 gene leading to craniosynostosis.

Dystrophinopathies which consist of Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD), are one of the most prevalent genetic disorders of childhood due to defect in a sarcolemmal protein called dystrophin. Its modern significance lies in the fact that they were one of the first hereditary disorders whose genetic basis was identified in the late 20th century and our knowledge in their genetics and pathophysiology has increased enormously since then. New treatments, such as corticosteroids, physical therapy, prosthetics and assisted ventilation can prolong survival. Still none of these factors have resulted in any major advances in treatment, and it remains, to this day an incurable disorder. Nevertheless, hope persists and investigators relentlessly pursue new ways for the treatment of Dystrophinopathies. Clinical, genetic and pathological aspects of the dystrophinopathies and the methods for diagnosis and treatment are reviewed in this article.

Systemic Lupus Erythematosus is a chronic autoimmune disorder that almost involves all of tissues and organs in body. The etiology of Lupus is mostly unknown. It seems that both genetic and environmental factores contribute in the disease development. Numerous genes have been suggested as candidate gene for Systemic Lupus Erythematosus, for example, the genes for apoptosis and genes for production of immune system. Linkage analysis is used to identify susceptibility genes for inherited diseases like Lupus. For this reason, the candidate genes and their polymorphism are evaluated in various populations. If finding can be repeated in an independent set of samples, the polymorphism causing genetic association with a candidate gene may identify the actual disease-causing gene. Linkage studies use a set of markers and different studies for the coinheritance of genetic markers with the disease phenotype in families lead us to the significant role of genetics in the development of SLE, disease association on a population basis, and once the power of the genetic analyses is correlated with the differences in the disease symptoms in different populations, we may have the ability to identify particular individuals as belonging to a specific subgroup with a predictable disease course. Finally understanding the genetics of SLE also should lead to more specific therapeutic interventions.

Prion diseases or transmissible spongiform encephalopathy are a group of human and animal fatal, infectious, neurodegenerative conditions, all which are incurable. The agent of disorder was unknown until 1987, but nowadays scientists believe that a protein is responsible for disease is not a nucleic acid (protein-only hypothesis). Human prion diseases can be classified as sporadic, hereditary or acquired. The cause of sporadic Creutzfeldt-Jakob disease (CJD) is unknown, hereditary cases are associated with mutations of the prion protein gene (PRNP) and acquired forms are caused by the transmission of infection from human to human or, as a zoonosis, from cattle to human. They classified as Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and Kuru in human and bovine spongiform encephalopathy (BSE), scraipie and chronic wasting disease (CWD) in animals.

In this study, we report a patient who was afflicted by Griscelli syndrome (GC) type II. GS II is an autosomal recessive disorder that is associated with silver-gray sheen of the hair and immunodeficiency. Mutation in RAB27A gene is responsible for this type of GS. The aim of this study is to investigate mutations in the RAB27A gene in a 3-year-old boy who was referred to our center with immunodeficiency, silvery gray sheen of the hair, fever and accelerated phase. He was the third child of consanguine parents. The first child is a 6-year-old healthy girl and the second one was a boy who had the same clinical features as the proband, and he died when he was 13-month-old. So far the most of Iranian patients have had mutation in exon 6 of RAB27A gene and this mutation we report has been seen just in Iranian patients.

CODAS is a syndrome consisting of cerebral, ocular, dental, auricular, and skeletal abnormalities. Patients with this syndrome have psychomotor delay, mental retardation, generalized hypotonia, cataract, ptosis, abnormally shaped teeth, malformed ears, deafness, grooved nasal tip, radiological findings of spondylo-epiphyseal dysplasia, with delayed skeletal maturation and coronal vertebral clefts and short stature. We report on an Iranian girl with features resembling CODAS syndrome. She presented with facial dysmorphism, cataract, abnormally shaped teeth, malformed ear, radiological findings of metaphysio–epiphyseal dysplasia and growth and developmental delay. The underlying defect responsible for CODAS syndrome remains unknown. Many of the features suggest a possible underlying collagen gene defect. The fact that this child is the product of consanguineous marriage suggests the possibility of autosomal recessive inheritance.

Seckel syndrome is a rare autosomal recessive disorder with a typical "bird-headed" appearance. It characterized by proportionate dwarfism, mental retardation, microcephaly, and growth retardation. In this article we introduce a 7-year-old girl with short stature, microcephaly and mental retardation. She had a characteristic face with receding forehead, prominent nose, micrognathia, low set ears, down slanting palpebral fissure.We believed, she suffers from Seckel Syndrome or bird-headed dwarfism syndrome.