Mahmoud F. Elsaid

Altered PLP1 splicing causes hypomyelination of early myelinating structures.

The objective of this study was to investigate the genetic etiology of the X‐linked disorder “Hypomyelination of Early Myelinating Structures” (HEMS).

Mutation in non-coding RNA, RNU12 causes early-onset cerebellar ataxia.

Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age.

Evaluation of SNP calling using single and multiple-sample calling algorithms by validation against array base genotyping and Mendelian inheritance

BackgroundWith diminishing costs of next generation sequencing (NGS), whole genome analysis becomes a standard tool for identifying genetic causes of inherited diseases. Commercial NGS service providers in general not only provide raw genomic reads, but further deliver SNP calls to their clients. However, the question for the user arises whether to use the SNP data as is, or process the raw sequencing data further through more sophisticated SNP calling pipelines with more advanced algorithms.ResultsHere we report a detailed comparison of SNPs called using the popular GATK multiple-sample calling protocol to SNPs delivered as part of a 40x whole genome sequencing project by Illumina Inc of 171 human genomes of Arab descent (108 unrelated Qatari genomes, 19 trios, and 2 families with rare diseases) and compare them to variants provided by the Illumina CASAVA pipeline. GATK multi-sample calling identifies more variants than the CASAVA pipeline. The additional variants from GATK are robust for Mendelian consistencies but weak in terms of statistical parameters such as TsTv ratio. However, these additional variants do not make a difference in detecting the causative variants in the studied phenotype.ConclusionBoth pipelines, GATK multi-sample calling and Illumina CASAVA single sample calling, have highly similar performance in SNP calling at the level of putatively causative variants.

W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report

BackgroundWW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death.Case presentationClinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death.Using Whole Exome Sequencing (WES), a novel homozygous mutation in the WWOX gene is identified in a consanguineous Arab family from Qatar with two daughters who presented with intractable seizure and developmental delay.ConclusionThe study presents the importance of human WWOX gene for brain development and the association between gene mutation and epileptic encephalopathy. It also highlights the power of WES particularly in clinically challenging cases.

Novel hypomyelinating leukoencephalopathy affecting early myelinating structures.

OBJECTIVE To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities. DESIGN In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. SUBJECTS The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations. RESULTS Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintense-hypointense-hyperintense stripes in 3 patients. The T1-weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. CONCLUSIONS The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelination.

Neuronal Ceroid Lipofuscinosis in Qatar: Report of a Novel Mutation in Ceroid-Lipofuscinosis, Neuronal 5 in the Arab Population

This study sought to genetically define the first family diagnosed with neuronal ceroid lipofuscinosis from Qatar. Onset was in late infancy (3 years), and sequencing in the affected children revealed a novel homozygous c.613C>T change in exon 3 of ceroid-lipofuscinosis, neuronal 5, corresponding to a missense mutation of a conserved amino acid, p.Pro205Ser. The clinical manifestations of the disease in this family largely resemble those of ceroid-lipofuscinosis, neuronal 5 disease, variant late infantile that was first described in Finland and include mental decline, visual deterioration, ataxia, and epileptic seizures. This description of ceroid-lipofuscinosis, neuronal 5 disease in an Arab family adds to the clinical and molecular diversity of the variant late-infantile neuronal ceroid lipofuscinoses, which were originally reported in Europe and are increasingly recognized in other populations.

Whole genome sequencing identifies a novel occludin mutation in microcephaly with band-like calcification and polymicrogyria that extends the phenotypic spectrum

Whole Genome Sequencing Identifies a Novel Occludin Mutation in Microcephaly With Band-Like Calcification and Polymicrogyria That Extends the Phenotypic Spectrum Mahmoud F. Elsaid, Hussein Kamel, Nader Chalhoub, Nahla Abdel Aziz, Khalid Ibrahim, Tawfeg Ben-Omran, Binu George, Eman Al-Dous, Yasmin Mohamoud, Joel A. Malek, M. Elizabeth Ross, and Alice Abdel Aleem* Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Weill Cornell Medical College, Qatar Department of Radiology, Hamad Medical Corporation, Doha, Qatar Laboratories Neurogenetics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar Center for Neurogenetics, Brain & Mind Research Institute, Weill Cornell Medical College, New York National Research Center, Cairo, Egypt Genomics Core, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar Department of Neurology, Brain & Mind Research Institute, Weill Cornell Medical College, New York

New subtype of familial intracranial calcification in a mother and two children

We report on a mother and two children from a consanguineous Arab Qatari family demonstrating a highly distinctive pattern of intracranial calcification involving the globus pallidus, posterior limb of the internal capsule, genu of the corpus callosum, and deep white matter. Both siblings, a girl and boy, presented with neonatal seizures without subsequent deterioration in neurological function. The girl demonstrated mild to moderate psychomotor delay but her brother and mother showed completely normal development. All three affected individuals were normocephalic. To the best of our knowledge this phenotype represents a novel disorder of inherited brain calcification, which may be recognizable on computerized tomography brain imaging in other cases. Although the disease shows apparent autosomal dominant inheritance, the high degree of consanguinity in the family leaves open the possibility of pseudo‐dominance for an autosomal recessive trait.

Non-truncating LIFR mutation: Causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi‐domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve–Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long‐term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

Oculo-ectodermal syndrome: A case report and further delineation of the syndrome

Oculo-ectodermal syndrome (OES - OMIM 600628), also known as Toriello Lacassie Droste syndrome, is a very rare condition, first described by Toriello et al., in 1993. OES has been proposed to be a mild variant of encephalocraniocutaneous lipomatosis (ECCL). It is characterized by aplasia cutis congenita (ACC), epibulbar dermoids, coarctation of the aorta, arachnoid cysts in the brain, seizure disorder, hyperpigmented nevi, non-ossifying fibromas and a predisposition to develop giant cell tumors of the jaw. There are few reported cases of OES worldwide but with no definite diagnostic criteria yet. We present a case in a child with unilateral hyperpigmented nevi and ACC on the scalp, ocular lesions (lipodermoid cysts and coloboma), temporal arachnoid cyst, spinal lipomatosis and aortic coarctation with the aim of enhancing the foundation to establish diagnostic criteria for this condition. It additionally serves as a teaching point to emphasize the importance of pursuing a definite diagnosis when faced with such a multisystem illness, to counsel patients and their parents regarding long term morbidity and overall prognosis.