Publications by authors named "Fatema Alzahrani"

33 Publications

Further delineation of SMG9-related heart and brain malformation syndrome.

Am J Med Genet A 2021 Feb 20. Epub 2021 Feb 20.

Department of Translational Genomics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1002/ajmg.a.62139DOI Listing
February 2021

Generation of iPSC lines (KAUSTi011-A, KAUSTi011-B) from a Saudi patient with epileptic encephalopathy carrying homozygous mutation in the GLP1R gene.

Stem Cell Res 2020 Dec 28;50:102148. Epub 2020 Dec 28.

Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia. Electronic address:

Glucagon-like peptide-1 receptor (GLP1R) is a seven-transmembrane-spanning helices membrane protein expressed in multiple human tissues including pancreatic islets, lung, brain, heart and central nervous system (CNS). GLP1R agonists are commonly used as antidiabetic drugs, but a neuroprotective function in neurodegenerative disorders is emerging. Here, we established two iPSC lines from a patient harboring a rare homozygous splice site variant in GLP1R (NM_002062.3; c.402 + 3delG). This patient displays severe developmental delay and epileptic encephalopathy. Therefore, the derivation of these iPSC lines constitutes a primary model to study the molecular pathology of GLP1R dysfunction and develop novel therapeutic targets.
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http://dx.doi.org/10.1016/j.scr.2020.102148DOI Listing
December 2020

A de novo ATXN2L variant in a child with developmental delay and macrocephaly.

Am J Med Genet A 2021 03 7;185(3):949-951. Epub 2020 Dec 7.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1002/ajmg.a.62007DOI Listing
March 2021

Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

Am J Hum Genet 2020 12 25;107(6):1178-1185. Epub 2020 Nov 25.

Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Deparment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820624PMC
December 2020

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.

Genome Biol 2020 06 17;21(1):145. Epub 2020 Jun 17.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce.

Results: Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all "solved" cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received "negative" clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders.

Conclusions: Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
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http://dx.doi.org/10.1186/s13059-020-02053-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298854PMC
June 2020

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

Hepatology 2020 Jun 20;71(6):2067-2079. Epub 2020 Feb 20.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background And Aims: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such.

Approach And Results: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system.

Conclusions: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.
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http://dx.doi.org/10.1002/hep.30982DOI Listing
June 2020

A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis.

Eur J Hum Genet 2020 04 30;28(4):525-528. Epub 2019 Sep 30.

Department of Pediatrics, Prince Sultan Military Medical City, Riyad, Saudi Arabia.

Congenital heart disease (CHD) is the most common type of birth defects with family- and population-based studies supporting a strong hereditary component. Multifactorial inheritance is the rule although a growing number of Mendelian forms have been described including candidates that have yet to be confirmed independently. TLL1 is one such candidate that was proposed in the etiology of atrial septal defect (ASD). We describe a girl with congenitally corrected transposition of the great arteries (ccTGA) and ASD secundum whose whole-exome sequencing (WES) revealed a de novo splicing (c.1379-2A>G) variant in TLL1 as well as an inherited truncating variant in NODAL. The identification of this dual molecular diagnosis both supports the candidacy of TLL1 in ASD pathogenesis and highlights the power of WES in revealing multilocus cardiac phenotypes.
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http://dx.doi.org/10.1038/s41431-019-0524-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080731PMC
April 2020

Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

Am J Hum Genet 2019 04 21;104(4):731-737. Epub 2019 Mar 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451727PMC
April 2019

Autozygome and high throughput confirmation of disease genes candidacy.

Genet Med 2019 03 21;21(3):736-742. Epub 2018 Sep 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

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.
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http://dx.doi.org/10.1038/s41436-018-0138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752307PMC
March 2019

Expanding the phenome and variome of skeletal dysplasia.

Genet Med 2018 12 5;20(12):1609-1616. Epub 2018 Apr 5.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.

Methods: Detailed phenotyping and next-generation sequencing (panel and exome).

Results: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.

Conclusion: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
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http://dx.doi.org/10.1038/gim.2018.50DOI Listing
December 2018

A mendelian form of neural tube defect caused by a de novo null variant in SMARCC1 in an identical twin.

Ann Neurol 2018 02 9;83(2):433-436. Epub 2018 Feb 9.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Neural tube defects (NTDs) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTDs are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTDs in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTDs (occipital encephalocele and myelomeningocele) and a shared de novo, likely truncating, variant in SMARCC1. RTPCR analysis suggests the potential null nature of the variant attributed to nonsense-mediated decay. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler, BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTDs in the form of exencephaly. This is the first report of SMARCC1 mutation in humans, and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. Ann Neurol 2018;83:433-436.
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http://dx.doi.org/10.1002/ana.25152DOI Listing
February 2018

Expanding the genetic heterogeneity of intellectual disability.

Hum Genet 2017 11 22;136(11-12):1419-1429. Epub 2017 Sep 22.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
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http://dx.doi.org/10.1007/s00439-017-1843-2DOI Listing
November 2017

GWAS signals revisited using human knockouts.

Genet Med 2018 01 22;20(1):64-68. Epub 2017 Jun 22.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.
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http://dx.doi.org/10.1038/gim.2017.78DOI Listing
January 2018

Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

Hum Genet 2016 May 29;135(5):525-540. Epub 2016 Mar 29.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.
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http://dx.doi.org/10.1007/s00439-016-1660-zDOI Listing
May 2016

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.

Genome Biol 2015 Dec 29;16:293. Epub 2015 Dec 29.

School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.

Background: Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures.

Results: Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions.

Conclusions: We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation.
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http://dx.doi.org/10.1186/s13059-015-0858-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699358PMC
December 2015

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.

Genet Med 2016 07 3;18(7):686-95. Epub 2015 Dec 3.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation.

Methods: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes.

Results: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort.

Conclusion: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.
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http://dx.doi.org/10.1038/gim.2015.147DOI Listing
July 2016

Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.

Am J Hum Genet 2015 Oct 10;97(4):608-15. Epub 2015 Sep 10.

Department of Genetics, King Faisal and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.
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http://dx.doi.org/10.1016/j.ajhg.2015.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596891PMC
October 2015

LOXL3, encoding lysyl oxidase-like 3, is mutated in a family with autosomal recessive Stickler syndrome.

Hum Genet 2015 Apr 7;134(4):451-3. Epub 2015 Feb 7.

Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03, PO BOX 3354, Riyadh, 11211, Saudi Arabia.

Stickler syndrome (SS) is a collagenopathy characterized by arthropathy and vitreoretinopathy with high myopia and cleft palate as common features. In a family with an autosomal recessive SS that does not map to genes known to cause autosomal recessive forms of SS, we combined autozygome and exome analysis to identify a novel missense variant in LOXL3 as the likely candidate cause. LOXL3 cross-links collagen II and its morphants phenocopy the craniofacial defects characteristic of collagen XI deficiency. We propose LOXL3 as a novel candidate gene for autosomal recessive SS.
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http://dx.doi.org/10.1007/s00439-015-1531-zDOI Listing
April 2015

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

Cell Rep 2015 Jan 31;10(2):148-61. Epub 2014 Dec 31.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. Electronic address:

Our 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.
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http://dx.doi.org/10.1016/j.celrep.2014.12.015DOI Listing
January 2015

Novel IFT122 mutation associated with impaired ciliogenesis and cranioectodermal dysplasia.

Mol Genet Genomic Med 2014 Mar 10;2(2):103-6. Epub 2013 Dec 10.

Department of Genetics, King Faisal Specialist Hospital and Research Center Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University Riyadh, Saudi Arabia.

Cranioectodermal dysplasia (CED) is a very rare autosomal recessive disorder characterized by a recognizable craniofacial profile in addition to ectodermal manifestations involving the skin, hair, and teeth. Four genes are known to be mutated in this disorder, all involved in the ciliary intraflagellar transport confirming that CED is a ciliopathy. In a multiplex consanguineous family with typical CED features in addition to intellectual disability and severe cutis laxa, we used autozygosity-guided candidate gene analysis to identify a novel homozygous mutation in IFT122, and demonstrated impaired ciliogenesis in patient fibroblasts. This report on IFT122 broadens the phenotype of CED and expands its allelic heterogeneity.
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http://dx.doi.org/10.1002/mgg3.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960051PMC
March 2014

Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation.

J Med Genet 2012 Oct;49(10):630-5

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases.

Methods: We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation.

Results: Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families.

Conclusions: TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.
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http://dx.doi.org/10.1136/jmedgenet-2012-101142DOI Listing
October 2012

Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism.

Hum Mutat 2012 Oct 30;33(10):1429-34. Epub 2012 Aug 30.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Primordial dwarfism (PD) is a clinically and genetically heterogeneous condition. Various molecular mechanisms are known to underlie the disease including impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA damage response, defective spliceosomal machinery, and abnormal replication licensing. Here, we describe a syndromic form of PD associated with severe intellectual disability and distinct facial features in a large multiplex Saudi family. Analysis reveals a novel underlying mechanism for PD involving depletion of 7SK, an abundant cellular noncoding RNA (ncRNA), due to mutation of its chaperone LARP7. We show that 7SK levels are tightly linked to LARP7 expression across cell lines, and that this chaperone is ubiquitously expressed in the mouse embryo. The 7SK is known to influence the expression of a wide array of genes through its inhibitory effect on the positive transcription elongation factor b (P-TEFb) as well as its competing role in HMGA1-mediated transcriptional regulation. This study documents a critical role played by ncRNA in human development and adds to the growing list of molecular mechanisms that, when perturbed, converge on the PD phenotype.
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http://dx.doi.org/10.1002/humu.22175DOI Listing
October 2012

Molecular characterization of Joubert syndrome in Saudi Arabia.

Hum Mutat 2012 Oct 11;33(10):1423-8. Epub 2012 Jul 11.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Joubert syndrome (JS) is a ciliopathy that is defined primarily by typical cerebellar structural and ocular motility defects. The genetic heterogeneity of this condition is significant with 16 genes identified to date. We have used a combination of autozygome-guided candidate gene mutation analysis and exome sequencing to identify the causative mutation in a series of 12 families. The autozygome approach identified mutations in RPGRIP1L, AHI1, TMEM237, and CEP290, while exome sequencing revealed families with truncating mutations in TCTN1 and C5ORF42. Our study, the largest comprehensive molecular series on JS, provides independent confirmation of the recently reported TCTN1, TMEM237, and C5ORF42 as bona fide JS disease genes, and expands the allelic heterogeneity of this disease.
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http://dx.doi.org/10.1002/humu.22134DOI Listing
October 2012

Autozygome maps dispensable DNA and reveals potential selective bias against nullizygosity.

Genet Med 2012 May 5;14(5):515-9. Epub 2012 Jan 5.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Copy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated.

Methods: We analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring.

Results: Analysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping "dispensable" DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages.

Conclusions: The autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals.
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http://dx.doi.org/10.1038/gim.2011.28DOI Listing
May 2012

Congenital disorder of glycosylation IIa: the trouble with diagnosing a dysmorphic inborn error of metabolism.

Am J Med Genet A 2012 Jan 21;158A(1):245-6. Epub 2011 Nov 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1002/ajmg.a.34347DOI Listing
January 2012

A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf.

Eur J Med Genet 2011 May-Jun;54(3):319-22. Epub 2011 Feb 26.

Département de Génétique, Université Paris Descartes, Unité INSERM U781, Hôpital Necker-Enfants Malades, 75015 Paris, France.

Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2A→G. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs).
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http://dx.doi.org/10.1016/j.ejmg.2011.01.009DOI Listing
September 2011