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1.  CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis 
Cell reports  2014;8(3):647-655.
Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intra-cellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.
PMCID: PMC4334362  PMID: 25066123
2.  SLC25A22 is a Novel Gene for Migrating Partial Seizures in Infancy 
Annals of neurology  2013;74(6):873-882.
To identify a genetic cause for migrating partial seizures in infancy (MPSI).
We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism (SNP) 500K data to identify regions with evidence for linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.
In a consanguineous pedigree with two individuals with MPSI, we identified two regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only one variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembraine domain of the protein, disrupts mitochondrial glutamate transport.
We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome neonatal epilepsy with suppression bursts on EEG, we have expanded the phenotypic spectrum associated with SLC25A22.
PMCID: PMC4031329  PMID: 24596948
3.  Congenital toxoplasmosis presenting as central diabetes insipidus in an infant: a case report 
BMC Research Notes  2014;7:184.
Congenital toxoplasmosis has a wide range of presentation at birth varying from severe neurological features such as hydrocephalus and chorioretinitis to a well appearing baby, who may develop complications late in infancy. While neuroendocrine abnormalities associated with congenital toxoplasmosis are uncommon, isolated central diabetes insipidus is extremely rare.
Case presentation
Here, we report on a female infant who presented with fever, convulsions, and polyuria. Examination revealed weight and length below the 3rd centile along with signs of severe dehydration. Fundal examination showed bilateral chorioretinitis. This infant developed hypernatremia together with increased serum osmolality and decreased both urine osmolality and specific gravity consistent with central diabetes insipidus. Serology for toxoplasma specific immunoglobulin M was high for both the mother and the baby and polymerase chain reaction for toxoplasma deoxyribonucleic acid was positive in the infant confirming congenital toxoplasmosis. Brain computerized tomography scans demonstrated ventriculomegaly associated with cerebral and cortical calcifications. Fluid and electrolyte abnormalities responded to nasal vasopressin therapy.
This report highlights central diabetes inspidus as a rare presentation of congenital toxoplasmosis.
PMCID: PMC3986852  PMID: 24674575
Congenital toxoplasmosis; Central diabetes insipidus; Infant
4.  Homozygous PLCB1 Deletion Associated with Malignant Migrating Partial Seizures in Infancy 
Epilepsia  2012;53(8):10.1111/j.1528-1167.2012.03538.x.
Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants (CNVs) genome-wide and long-range PCR to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.
PMCID: PMC3851296  PMID: 22690784
Focal epilepsy; migrating partial seizures in infancy; genetics; phospholipase C beta 1 (PLCB1)
6.  New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations 
PLoS ONE  2013;8(10):e76831.
Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients’ muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.
PMCID: PMC3792983  PMID: 24130795
7.  Congenital myasthenic syndromes due to mutations in ALG2 and ALG14 
Brain  2013;136(3):944-956.
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.
PMCID: PMC3580273  PMID: 23404334
congenital myasthenic syndrome; ALG2; ALG14; mutation; N-linked glycosylation
8.  The Clinical Spectrum of Homozygous HOXA1 Mutations 
We report nine new individuals from six families who have homozygous mutations of HOXA1 with either the Bosley-Salih-Alorainy Syndrome (BSAS) or the Athabascan Brainstem Dysgenesis Syndrome (ABDS). Congenital heart disease was present in four BSAS patients, two of whom had neither deafness nor horizontal gaze restriction. Two ABDS probands had relatively mild mental retardation. These individuals blur the clinical distinctions between the BSAS and ABDS HOXA1 variants and broaden the phenotype and genotype of the homozygous HOXA1 mutation clinical spectrum.
PMCID: PMC3517166  PMID: 18412118
9.  A novel syndrome of lethal familial hyperekplexia associated with brain malformation 
BMC Neurology  2012;12:125.
Hyperekplexia (HPX) is a rare non-epileptic disorder manifesting immediately after birth with exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, and non-habituating generalized flexor spasm in response to tapping of the nasal bridge (glabellar tap) which forms its clinical hallmark. The course of the disease is usually benign with spontaneous amelioration with age. The disorder results from aberrant glycinergic neurotransmission, and several mutations were reported in the genes encoding glycine receptor (GlyR) α1 and β subunits, glycine transporter GlyT2 as well as two other proteins involved in glycinergic neurotransmission gephyrin and collybistin.
The phenotype of six newborns, belonging to Saudi Arabian kindred with close consanguineous marriages, who presented with hyperekplexia associated with severe brain malformation, is described. DNA samples were available from two patients, and homozygosity scan to determine overlap with known hyperkplexia genes was performed.
The kindred consisted of two brothers married to their cousin sisters, each with three affected children who presented antenatally with excessive fetal movements. Postnatally, they were found to have microcephaly, severe hyperekplexia and gross brain malformation characterized by severe simplified gyral pattern and cerebellar underdevelopment. The EEG was normal and they responded to clonazepam. All of the six patients died within six weeks. Laboratory investigations, including metabolic screen, were unremarkable. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available.
We present these cases as a novel syndrome of lethal familial autosomal recessive hyperekplexia associated with microcephaly and severe brain malformation.
PMCID: PMC3488335  PMID: 23101555
Hyperekplexia; Microcephaly; Simplified gyral pattern; Cerebellar underdevelopment; Autosomal recessive
10.  Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2 
BMC Research Notes  2011;4:534.
Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.
We investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.
A previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.
Our data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.
PMCID: PMC3278494  PMID: 22166137
MDC1A; LAMA2; gene; Laminin α2 chain; Merosin
11.  Molecular and neurological characterizations of three Saudi families with lipoid proteinosis 
BMC Medical Genetics  2011;12:31.
Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families.
Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene.
All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8.
These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.
PMCID: PMC3050790  PMID: 21349189
12.  A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype-phenotype correlation 
BMC Medical Genetics  2010;11:135.
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.
We identified a potential ASD locus (9p24.3 to 9p23) that may encompass gene(s) contributing to autism or ASD.
PMCID: PMC2946294  PMID: 20858261
13.  Efficient identification of novel mutations in patients with limb girdle muscular dystrophy 
Neurogenetics  2010;11(4):449-455.
Limb girdle muscular dystrophy type 2 (LGMD2) is a genetically heterogeneous autosomal recessive disorder caused by mutations in 15 known genes. DNA sequencing of all candidate genes can be expensive and laborious, whereas a selective sequencing approach often fails to provide a molecular diagnosis. We aimed to efficiently identify pathogenic mutations via homozygosity mapping in a population in which the genetics of LGMD2 has not been well characterized. Thirteen consanguineous families containing a proband with LGMD2 were recruited from Saudi Arabia, and for 11 of these families, selected individuals were genotyped at 10,204 single nucleotide polymorphisms. Linkage analysis excluded all but one or two known genes in ten of 11 genotyped families, and haplotype comparisons between families allowed further reduction in the number of candidate genes that were screened. Mutations were identified by DNA sequencing in all 13 families, including five novel mutations in four genes, by sequencing at most two genes per family. One family was reclassified as having a different myopathy based on genetic and clinical data after linkage analysis excluded all known LGMD2 genes. LGMD2 subtypes A and B were notably absent from our sample of patients, indicating that the distribution of LGMD2 mutations in Saudi Arabian families may be different than in other populations. Our data demonstrate that homozygosity mapping in consanguineous pedigrees offers a more efficient means of discovering mutations that cause heterogeneous disorders than comprehensive sequencing of known candidate genes.
Electronic supplementary material
The online version of this article (doi:10.1007/s10048-010-0250-9) contains supplementary material, which is available to authorized users.
PMCID: PMC2944962  PMID: 20623375
Limb girdle muscular dystrophy; Mutations; Linkage analysis; Homozygosity mapping; Consanguineous; Saudi Arabian
14.  Ethnically Diverse Causes of Walker-Warburg Syndrome (WWS): FCMD Mutations Are a More Common Cause of WWS Outside of the Middle East 
Human mutation  2008;29(11):E231-E241.
Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
PMCID: PMC2577713  PMID: 18752264
Walker-Warburg syndrome; congenital muscular dystrophy; alpha-dystroglycan; POMT1, POMT2, FCMD, FKRP
15.  Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis 
Science (New York, N.Y.)  2004;304(5676):1509-1513.
The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.
PMCID: PMC1618874  PMID: 15105459
16.  Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome 
Human Genetics  2007;121(6):685-690.
Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of α-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual α-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the α-dystroglycan protein.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-007-0362-y) contains supplementary material, which is available to authorized users.
PMCID: PMC1914248  PMID: 17436019

Results 1-16 (16)