Partial duplication of chromosome 19 associated with syndromic duane retraction syndrome.

BACKGROUND: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome, modest dysmorphism, cerebral white matter abnormalities, and normal cognitive function. MATERIALS AND METHODS: Performing high-resolution array comparative genomic hybridization (array CGH) and sequencing of HOXA1, KIF21A, SALL4, and CHN1 genes. RESULTS: The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood. Motor development and cognitive function were normal. Parents were not related, and no other family member was similarly affected. MRI revealed multiple small areas of high signal on T2 weighted images in cerebral white matter oriented along white matter tracts. Sequencing of HOXA1, KIF21A, SALL4, and CHN1 did not reveal any mutation(s). Array CGH showed a 95 Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes. Conclusions. KIR genes have not previously been linked to a developmental syndrome, although they are known to be expressed in the human brain and brainstem and to be associated with certain infections and autoimmune diseases, including some affecting the nervous system. DRS and brain neuroimaging abnormalities may imply a central and peripheral oligodendrocyte abnormality related in some fashion to an immunomodulatory disturbance.

Nicotinic Receptor Mutation in a Mildly Dysmorphic Girl with Duane Retraction Syndrome.

BACKGROUND: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome and modest dysmorphism. MATERIALS AND METHODS: Clinical evaluation, sequencing of candidate genes, and array comparative genomic hybridization (array CGH). RESULTS: The proband had unilateral Duane retraction syndrome (DRS) with low-set ears bilaterally, a high arched palate, and clinodactyly. Motor development and cognitive function were normal. Parents were first cousins, but no other family member was similarly affected. No mutations were detected in the HOXA1. KIF21A. SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 16 Kb de novo deletion at chromosome 8p11.2 that encompassed a portion of only one gene, the Cholinergic Receptor, Nicotinic, Beta-3 (CHRNB3, Neuronal). This gene encodes a protein that is involved in the nicotinic acetylcholine receptor on neurons. It interacts functionally with other genes that code components of the acetylcholine receptor. CONCLUSIONS: This patient's chromosomal abnormality affected only one gene that is highly expressed in the brainstem and brain, involved in neurotransmission, and could be related to her Duane retraction syndrome.

Clinical and molecular characterization of maturity onset-diabetes of the young caused by hepatocyte nuclear factor-4 alpha mutation: red flags for prediction of the diagnosis.

BACKGROUND AND OBJECTIVES: The prevalence of maturity-onset diabetes of the young (MODY) in Saudi population remains unknown, and data on molecular etiology of this condition is limited. Therefore, the present study was undertaken to elucidate clinical and molecular characteristics of a Saudi family with MODY 1. DESIGN AND SETTINGS: This is a case series study conducted at Saad Specialist Hospital in Alkhobar, Saudi Arabia. PATIENTS AND METHODS: A 12-year-old female presented to us with symptoms suggestive of diabetes. Investigations revealed hyperglycemia, glycosuria, and ketonuria without acidosis. Pancreatic antibodies were negative. She responded well to subcutaneous insulin. Her family history revealed that 2 of her siblings were diagnosed with type 1 diabetes (T1DM), while her father and mother had type 2 diabetes (T2DM). In view of this strong family history, the possibility of monogenic diabetes was raised, and the 2 genes consistent with this phenotype, hepatocyte nuclear factor-1 alpha (HNF1a) and hepatocyte nuclear factor-4 alpha (HNF4a), were studied. Accordingly, genomic DNA was isolated from peripheral blood lymphocytes of the 8 members of this family, polymerase chain reaction was carried out, and sequencing of the whole HNF4a and HNF1a genes was done. RESULTS: DNA study of the proband revealed a heterozygous substitution in intron 1 (IVS1b C > T-5)(c.50-5C > T) of the HNF1a gene. This mutation was identified in other 5 members of the family. CONCLUSION: This study alerts physicians to suspect MODY in patients who have a strongly positive family history of diabetes over a few generations with negative pancreatic antibodies and absence of ketoacidosis and obesity.

Neurologic injury in isolated sulfite oxidase deficiency.

BACKGROUND: We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). METHODS: All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. RESULTS: Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. CONCLUSIONS: ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.Lésions neurologiques dans le déficit isolé en sulfite oxydase.

Ophthalmologic observations in a patient with partial mosaic trisomy 8.

BACKGROUND: To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features. METHODS: Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH). RESULTS: The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm. CONCLUSIONS: This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.

Successful pregnancies after combined human leukocyte antigen direct genotyping and preimplantation genetic diagnosis utilizing multiple displacement amplification.

OBJECTIVE: To devise a new and simple technique to help select normal embryos that are human leukocyte antigen (HLA) matched to their affected siblings for diseases, such as beta-thalassemia or sickle cell anemia, which are common in this part of the world. METHODS: This study was conducted between March 2008 and April 2011 at the preimplantation Genetic Diagnosis Laboratory, Saad Specialist Hospital, Al-Khobar, Kingdom of Saudi Arabia. Embryos were obtained after 7 in vitro fertilization preimplantation genetic diagnosis (IVF-PGD) cycles. Single cells were biopsied, and extracted DNA was amplified by the multiple displacement amplification (MDA) technique. Amplified DNA was then tested for mutations in the beta-globin gene, and directly HLA typed using a sequence specific primer technique. RESULTS: We report 7 families that underwent 7 PGD cycles with HLA typing and direct HLA loci-typing using an HLA conventional commercial kit. Two patients had PGD and HLA typing for class I and II, while the other 5 had class II. The PGD cycles resulted in 3 pregnancies out of 5 patients who had HLA matched and normal embryos. One family had a successful hematopoietic stem cell transplant. CONCLUSION: This report demonstrates the first clinical application of PGD coupled with direct HLA loci-typing of DNA amplified by MDA from a single cell.

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus.

PURPOSE: To determine whether patients with sporadic, non-familial keratoconus and no pathogenic mutations in the visual system homeobox 1 (VSX1) gene have evidence of chromosomal copy number alterations. METHODS: Twenty Saudi Arabian patients with isolated keratoconus, no family history of the disease and no mutations in VSX1 were recruited. Additionally, 10 ethnically-matched healthy controls were also recruited for this study. We screened patients for chromosomal copy number aberrations using the Agilent Human Genome CGH 244A Oligo Microarray Chip. RESULTS: None of the keratoconus patients screened had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. CONCLUSIONS: Chromosomal deletions and/or duplications were not detected in any of the patients tested here. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array CGH technology and other nuclear genetic or epigenetic factors cannot be excluded as a possible contributing factor to keratoconus pathogenesis.

A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype-phenotype correlation.

BACKGROUND: Previous studies focusing on candidate genes and chromosomal regions identified several copy number variations (CNVs) associated with increased risk of autism or autism spectrum disorders (ASD). CASE PRESENTATION: We describe a 17-year-old girl with autism, severe mental retardation, epilepsy, and partial 9p duplication syndrome features in whom GTG-banded chromosome analysis revealed a female karyotype with a marker chromosome in 69% of analyzed metaphases. Array CGH analysis showed that the marker chromosome originated from 9p24.3 to 9p13.1 with a gain of 38.9 Mb. This mosaic 9p duplication was detected only in the proband and not in the parents, her four unaffected siblings, or 258 ethnic controls. Apart from the marker chromosome, no other copy number variations (CNVs) were detected in the patient or her family. Detailed analysis of the duplicated region revealed: i) an area extending from 9p22.3 to 9p22.2 that was previously identified as a critical region for the 9p duplication syndrome; ii) a region extending from 9p22.1 to 9p13.1 that was previously reported to be duplicated in a normal individual; and iii) a potential ASD locus extending from 9p24.3 to 9p23. The ASD candidate locus contained 34 genes that may contribute to the autistic features in this patient. CONCLUSION: We identified a potential ASD locus (9p24.3 to 9p23) that may encompass gene(s) contributing to autism or ASD.

Hemoglobin D/beta-thalassemia and beta-thalassemia major in a Saudi family.

The present report describes the clinical, hematological and molecular characteristics in a family with unique interaction between 3 different mutations discovered during routine workup for bone marrow transplantation. In this report, complete hematological and molecular studies were performed for a large Saudi family. The family consisted of parents and 9 children, which revealed that the father is compound heterozygous for hemoglobin Hb D Punjab/beta-thalassemia, the mother is a carrier for beta-thalassemia and 3 of their children are transfusion dependent beta-thalassemia. Two of the children are compound heterozygous for Hb D Punjab/beta-thalassemia like the father but with different genotype. The other 2 children have Hb D Punjab traits while 2 other children have beta-thalassemia traits. Although, compound heterozygous for Hb D/beta-thalassemia has been well described in the literature, our report emphasizes the importance of careful analysis of the electrophoresis results and the usefulness of molecular studies in premarital screening and other screening hemoglobinopathy programs.

Recently available techniques applicable to genetic problems in the Middle East.

In this paper, we address the preventive health aspects of genetic problems in the Middle East and provide guidelines to prioritize preventive strategies. Applications of various novel genetic techniques such as comprehensive neonatal screening, high throughput heterozygote detection, preimplantation genetic diagnosis, Affymetrix systems, the NanoChip system and a new way of sensitive karyotyping for single-cell chromosome abnormalities are discussed. In conclusion, from the various genetic techniques available, each country should adopt strategies most suitable to its genetic needs and should prioritize the programs to be used in prevention.

A new era for preventive genetic programs in the Arabian Peninsula.

In the Arabian Peninsula, high percentages of consanguineous marriages and the tribal nature of marriages have resulted in high incidence of genetically based disorders. The successful management of these disorders incurs a high financial cost, which is a great burden on the health care system. The practical solution to this problem is through prevention. Prevention of genetic disorders should be the utmost public health concern especially where these disorders are prevalent. Preventive genetics became possible with the advent of biochemical and molecular technologies. Biochemical neonatal screening based on tandem mass spectrometry technology and molecular technologies such as sequencing, DNA microarray and nucleic acid hybridization techniques are steadily being transferred to clinical practice. Preventive genetics could be best achieved through establishment of databases for common genetic disorders, premarital diagnosis, and pre-implantation genetic diagnosis and by genetic counseling. These preventive measures must take into account the social and cultural aspects.