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Purpose Whole-exome sequencing (WES) can help identify known and novel pathogenic molecular aberrations. Here, we examined the diagnostic yield of WES in population from consanguineous unions. Methods We preformed retrospective review of multicenter WES results of an unselected cohort of patients with a wide range of phenotypes. Clinical data and WES reports of 454 patients from 5 centers across Saudi Arabia were analyzed. Testing was performed in accredited commercial laboratories, and all the WES laboratory reports were reviewed again using additional clinical information available to the treating physicians. Results Among the 454 probands, we identified highly likely disease-causing variants in 222, thereby achieving a 49% molecular diagnostic yield. The diagnostic yield was 53% in consanguineous unions and 39% in non-consanguineous unions. About 66% of the identified variants in consanguineous families were homozygous, with an autosomal recessive mode of inheritance. Additional clinical data reclassified 11 positive reported results into 4 inconclusive and 7 negative results, and 22 inconclusive results into 17 positive and 5 negative results. Conclusions The diagnostic yield from WES in our unselected cohort is similar to other studies from the same region, which is a higher yield compared to other international regions largely because of the high rate of consanguinity and partly due to simplified variant interpretation and classification in consanguineous unions.

Background Mutations in AFG3L2 , a gene encoding a subunit of the mitochondrion m-AAA protease, cause spinocerebellar ataxia type 28 and recessive spastic ataxia type 5. Neuroimaging shows cerebellar atrophy. Methods Retrospective review of the patient charts including their clinical evaluation and molecular genetic, neurodiagnostic, and neuroradiological investigations. Results We describe five members of a large consanguineous family with a severe mitochondrial disease phenotype in the form of regression of the developmental milestones in the first year of life, refractory epilepsy, progressive microcephaly, increased blood lactate, basal ganglia involvement, and premature death. Exome sequencing showed homozygous mutation of the AFG3L2 gene in all individuals: c.1714G>A (p.Ala572Thr). Conclusions Our findings add to the phenotypic, neuroradiological, genetic, and biochemical spectrum of AFG3L2 mutations.

Acute weakness and dyspnoea are unusual presentation after allogeneic haematopoietic stem cell transplantation (HSCT) complicated by chronic graft-versus-host disease (GVHD). The differential diagnosis and management are challenging for the paediatrician. This case chronicles the diagnostic journey of a child who presented with weakness, dyspnoea and difficulty in speech, 2 years after allogeneic HSCT and GVHD and explores the approach to neurological manifestations in this context.

Background Mutations in AIMP1, which plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments, cause neurodegeneration of variable severity and white matter abnormalities. Methods From the patient records we analyzed the clinical evaluation, molecular genetics, neurodiagnostic, and neuroradiological investigations. Results We describe six members of a large consanguineous family with a phenotype of severe neurodegeneration in the form of developmental delays, progressive microcephaly, epilepsy, and failure to thrive. MRI showed callosal atrophy and T2 hyperintensity in the superficial white matter. The periventricular and deep white matter structures were, however, preserved. MR spectroscopy demonstrated N-acetylaspartate preservation without evidence of neuroinflammation. Exome sequencing showed a novel homozygous mutation of the AIMP1 gene in all individuals: c.917A>G (p.(Asp306Gly)). Conclusions This novel homozygous mutation of the AIMP1 gene is characterized by preserved development of the periventricular and deep white matter structures as demonstrated by MRI and MR spectroscopy correlation.

Purpose Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. Methods Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. Conclusions Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Çalışmada 47 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect. King Salman Center for Disability Research Saudi Human Genome Program Howard Hughes Medical Institute National Institute of Neurological Disorders and Stroke Manton Center for Orphan Disease Research, Boston Children's Hospital King Abdullah University of Science and Technology King Abdulaziz City for Science and Technology Deanship of Scientific Research, King Saud University

Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting. © 2015 Wiley Periodicals, Inc.

Objective To compare the combination of biotin plus thiamine to thiamine alone in treating patients with biotin-responsive basal ganglia disease in an open-label prospective, comparative study. Methods twenty patients with genetically proven biotin-responsive basal ganglia disease were enrolled, and received for at least 30 months a combination of biotin plus thiamine or thiamine alone. The outcome measures included duration of the crisis, number of recurrence/admissions, the last neurological examination, the severity of dystonia using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), and the brain MRI findings during the crisis and after 30 months of follow-up. Results Ten children with a mean age of 6 years1/2 were recruited in the biotin plus thiamine group (group 1) and ten children (6 females and 4 males) with a mean age of 6 years and 2 months were recruited in the thiamine group (group 2). After 2 years of follow-up treatment, 6 of 20 children achieved complete remission, 10 had minimal sequelae in the form of mild dystonia and dysarthria (improvement of the BFMDRS, mean: 80%), and 4 had severe neurologic sequelae. All these 4 patients had delayed diagnosis and management. Regarding outcome measures, both groups have a similar outcome regarding the number of recurrences, the neurologic sequelae (mean BFMDS score between the groups, p = 0.84), and the brain MRI findings. The only difference was the duration of the acute crisis: group 1 had faster recovery (2 days), versus 3 days in group 2 (p = 0.005). Conclusion Our study suggests that over 30 months of treatment, the combination of biotin plus thiamine is not superior to thiamine alone in the treatment of biotin-responsive basal ganglia disease.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.

We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.

Objective: To investigate the clinical, genetic, and neuroradiologic data of biotin-responsive basal ganglia disease (BBGD) and clarify the disease spectrum. Methods: We first investigated all patients attending our Division of Pediatric Neurology with a genetically proven diagnosis of BBGD between 2009 and 2011. All patients underwent a detailed medical history and clinical examination, extensive laboratory investigations including genetic tests, and brain MRI. Finally, we conducted a systematic review of the literature. Results: We enrolled 10 patients meeting the diagnostic criteria for BBGD, and analyzed the data on 14 patients from 4 previous reports. The BBGD occurred predominantly in preschool/school-aged patients in the Saudi population, but it was also observed in other ethnic groups. The typical clinical picture consisted of recurrent subacute encephalopathy leading to coma, seizures, and extrapyramidal manifestations. The brain MRI typically showed symmetric and bilateral lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and in the brainstem. Vasogenic edema characterized the acute crises as demonstrated by diffusion-weighted imaging/apparent diffusion coefficient MRI. Atrophy and gliosis in the affected regions were observed in patients with chronic disease. Early treatment with a combination of biotin and thiamine resulted in clinical and neuroradiologic improvement. Death and neurologic sequelae including dystonia, mental retardation, and epilepsy were observed in those who were not treated or were treated late. Conclusion: BBGD is an underdiagnosed pan-ethnic treatable condition. Clinicians caring for patients with unexplained encephalopathy and neuroimaging showing vasogenic edema in the bilateral putamen and caudate nuclei, infra- and supratentorial cortex, and brainstem should consider this disorder early in the hospital course because a therapeutic trial with biotin and thiamine can be lifesaving.

Background Sepiapterin reductase deficiency is a rare, under-recognized, autosomal recessively inherited disorder of neurotransmitter metabolism. Case report Five new patients from 3 unrelated Saudi consanguineous families are reported. Symptoms began at 6 months, with delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including axial hypotonia, dystonia, and cognitive impairment, associated with hyper-reflexia (4 patients), spasticity (4 patients), bulbar dysfunction (4 patients), and oculogyric crisis (2 patients) with diurnal fluctuation and sleep benefit. Cerebrospinal fluid neurotransmitters analysis showed a typical pattern with increased sepiapterin and increased 7,8-dihydrobiopterin. Analysis of the SPR gene identified 3 novel mutations: c.1A > G, c.370T > C, and c.527C > T. Patient one, with early diagnosis, is currently developing within the normal range. The 4 other patients showed significant improvement in their motor function, but only mild improvement in their cognitive dysfunction. Conclusion Our cases illustrate the difficulties in the diagnosis of sepiapterin reductase deficiency in infancy, and the importance of early recognition and management.

ALG9-CDG is one of the less frequently reported types of CDG. Here, we summarize the features of six patients with ALG9-CDG reported in the literature and report the features of four additional patients. The patients presented with drug-resistant infantile epilepsy, hypotonia, dysmorphic features, failure to thrive, global developmental disability, and skeletal dysplasia. One patient presented with nonimmune hydrops fetalis. A brain MRI revealed global atrophy with delayed myelination. Exome sequencing identified a novel homozygous mutation c.1075G>A, p.E359K of the ALG9 gene. The results of our analysis of these patients expand the knowledge of ALG9-CDG phenotype.

Molybdenum cofactor and isolated sulphite oxidase deficiencies are two related rare autosomal recessive diseases characterized by severe neurological abnormalities, dislocated lens and mental retardation. Determination of three biochemical markers S-sulphocysteine (SSC), xanthine (XAN) and hypoxanthine (HXAN) in urine is essential for a definitive diagnosis and identification of the exact defect. We developed a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of SSC, XAN and HXAN in urine. The analysis was carried out in the negative-ion selected-reaction monitoring mode. The turnaround time for the assay was 7 min. Linear calibration curves for the three biomarkers were obtained in the range of 12-480 micromol/L. The intra- and inter-day assay variations were

The temporal relationship between convulsive seizures and the administration of beta-lactams has long been recognized. A specific form of seizures, nonconvulsive status epilepticus, is less common and is often manifested by alterations in mental status without associated seizures. It is most commonly encountered in uremic patients and poses a diagnostic challenge because of its nonspecific clinical manifestations. In this report, we describe a child with chronic renal failure who developed nonconvulsive status epilepticus on two separate occasions after administration of a third-generation cephalosporin. Awareness of this potentially treatable condition is crucial to ensure appropriate and prompt medical therapy. To our knowledge, this is the first report of cephalosporin-induced nonconvulsive status epilepticus in a child with chronic renal failure.

SummaryOur knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

A 10-year-old girl with a 4-month history of abnormal gait and dysarthria was admitted to the hospital with altered mental status that had progressed over the previous 3 days in the context of febrile illness. The patient’s family reported that she did not use drugs, and the family history is remarkable only for consanguinity. On physical examination, she was confused, having generalized dystonia and bilateral external ophthalmoplegia, and she was anarthric. The results of toxicologic and autoimmune, cerebrospinal fluid, thyroid, bacterial and viral, and metabolic studies, in

Cytochrome c oxidase (COX) deficiency, one of the most common respiratory-chain defects in humans, has been associated with mutations in either mitochondrial DNA genes or nucleus-encoded proteins that are not part in but promote the biogenesis of COX. Mutations of nucleus-encoded structural subunits were sought for but never found in COX-defective patients, leading to the conjecture that they may be incompatible with extra-uterine survival. We report a disease-associated mutation in one such subunit, COX6B1. Nuclear-encoded COX genes should be reconsidered and included in the diagnostic mutational screening of human disorders related to COX deficiency.