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Article ; Online: Genomic analysis of presumed perinatal stroke in Saudi Arabia reveals a strong monogenic contribution.

Alshammari, Muneera J / Shamseldin, Hanan E / Essbaiheen, Fahad / Eltahir, Sara H / Alruwaili, Ashwag R / Abdulwahab, Firdous / Alkuraya, Fowzan S

Human genetics

2024 Volume 143, Issue 1, Page(s) 59–69

Abstract: Perinatal stroke is associated with significant short- and long-term morbidity and has been recognized as the most common cause of cerebral palsy in term infants. The diagnosis of presumed perinatal stroke (PPS) is made in children who present with ... ...

Abstract	Perinatal stroke is associated with significant short- and long-term morbidity and has been recognized as the most common cause of cerebral palsy in term infants. The diagnosis of presumed perinatal stroke (PPS) is made in children who present with neurological deficit and/or seizures attributable to focal chronic infarction on neuroimaging and have uneventful neonatal history. The underlying mechanism of presumed perinatal stroke remains unknown and thorough investigation of potential monogenic causes has not been conducted to date. Here, we describe the use of untargeted exome sequencing to investigate a cohort of eight patients from six families with PPS. A likely deleterious variant was identified in four families. These include the well-established risk genes COL4A2 and JAM3. In addition, we report the first independent confirmation of the recently described link between ESAM and perinatal stroke. Our data also highlight NID1 as a candidate gene for the condition. This study suggests that monogenic disorders are important contributors to the pathogenesis of PPS and should be investigated by untargeted sequencing especially when traditional risk factors are excluded.
MeSH term(s)	Infant ; Infant, Newborn ; Child ; Pregnancy ; Female ; Humans ; Saudi Arabia ; Stroke/genetics ; Stroke/diagnosis ; Neuroimaging/adverse effects ; Genomics ; Risk Factors
Language	English
Publishing date	2024-01-05
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-023-02621-6
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Article ; Online: Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve--Melchior--Clausen locus.

Alshammari, Muneera J / Al-Otaibi, Lefian / Alkuraya, Fowzan S

Journal of medical genetics

2012 Volume 49, Issue 7, Page(s) 455–461

Abstract: Background: Dyggve--Melchior--Clausen syndrome (DMC) is a chondrodysplasia that bears significant phenotypic resemblance to mucopolysaccharidosis type IV (Morquio disease). Autosomal recessive mutations in DYM are known to cause this disease through its ...

Abstract	Background: Dyggve--Melchior--Clausen syndrome (DMC) is a chondrodysplasia that bears significant phenotypic resemblance to mucopolysaccharidosis type IV (Morquio disease). Autosomal recessive mutations in DYM are known to cause this disease through its role in Golgi organisation and intracellular traffic, but genetic heterogeneity is suspected. Methods: A family with DMC and normal intellectual development underwent clinical evaluation followed by autozygosity mapping and exome sequencing. Immunoblot and immunofluorescence analyses were performed to characterise the effect of the mutation. Results: This multiplex consanguineous family links to a novel locus on 4q31.1. Exome sequencing revealed a missense mutation in RAB33B, which encodes a Rab protein with an established role in retrograde Golgi traffic. The mutation qualitatively replaces the invariant lysine residue in the guanine nucleotide-binding domain of this small GTPase protein and leads to marked protein deficiency, making it the likely causative mutation of DMC in this family. Conclusion: This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease.
MeSH term(s)	Adult ; Child ; Child, Preschool ; Consanguinity ; Cytoplasm/genetics ; Cytoplasm/metabolism ; Dwarfism/genetics ; Exome ; Female ; Fluorescent Antibody Technique/methods ; Genes, Recessive ; Genetic Diseases, X-Linked/genetics ; Genetic Heterogeneity ; Genetic Linkage ; Genetic Loci ; Genotype ; Golgi Apparatus/genetics ; Golgi Apparatus/metabolism ; Humans ; Intellectual Disability/genetics ; Male ; Mucopolysaccharidosis IV/genetics ; Mucopolysaccharidosis IV/physiopathology ; Mutation ; Osteochondrodysplasias/congenital ; Osteochondrodysplasias/genetics ; Pedigree ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
Chemical Substances	RAB33B protein, human (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2012-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2011-100666
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Article ; Online: Molecular pathogenesis of fibrochondrogenesis: is it really simple COL11A1 deficiency?

Alzahrani, Fatema / Alshammari, Muneera J / Alkuraya, Fowzan S

Gene

2012 Volume 511, Issue 2, Page(s) 480–481

MeSH term(s)	Abnormalities, Multiple/genetics ; Child ; Collagen Type XI/genetics ; Dwarfism/genetics ; Facies ; Humans ; Male ; Mutation, Missense
Chemical Substances	COL11A1 protein, human ; Collagen Type XI
Language	English
Publishing date	2012-12-15
Publishing country	Netherlands
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2012.09.069
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Article ; Online: Mutations in TMEM231 cause Meckel-Gruber syndrome.

Shaheen, Ranad / Ansari, Shinu / Mardawi, Elham Al / Alshammari, Muneera J / Alkuraya, Fowzan S

Journal of medical genetics

2013 Volume 50, Issue 3, Page(s) 160–162

Abstract: Background: Meckel-Gruber syndrome (MKS) is a genetically heterogeneous severe ciliopathy characterised by early lethality, occipital encephalocele, polydactyly, and polycystic kidney disease.: Purpose: To report genetic analysis results in two ... ...

Abstract	Background: Meckel-Gruber syndrome (MKS) is a genetically heterogeneous severe ciliopathy characterised by early lethality, occipital encephalocele, polydactyly, and polycystic kidney disease. Purpose: To report genetic analysis results in two families in which all known MKS diseases genes have been excluded. Methods: In two consanguineous families with classical MKS in which autozygome-guided sequencing of previously reported MKS genes was negative, we performed exome sequencing followed by autozygome filtration. Results: We identified one novel splicing mutation in TMEM231, which led to complete degradation of the mutant transcript in one family, and a novel missense mutation in the other, both in the homozygous state. Conclusions: TMEM231 represents a novel MKS locus. The very recent identification of TMEM231 mutations in Joubert syndrome supports the growing appreciation of the overlap in the molecular pathogenesis between these two ciliopathies.
MeSH term(s)	Abortion, Spontaneous ; Amino Acid Sequence ; Ciliary Motility Disorders/genetics ; Consanguinity ; Encephalocele/genetics ; Female ; Humans ; Male ; Membrane Proteins/genetics ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Polycystic Kidney Diseases/genetics ; Pregnancy ; Retinitis Pigmentosa ; Sequence Alignment
Chemical Substances	Membrane Proteins ; TMEM231 protein, human
Language	English
Publishing date	2013-01-24
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2012-101431
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Article ; Online: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

Mohamed, Jawahir Y / Faqeih, Eissa / Alsiddiky, Abdulmonem / Alshammari, Muneera J / Ibrahim, Niema A / Alkuraya, Fowzan S

American journal of human genetics

2013 Volume 92, Issue 1, Page(s) 157–161

Abstract: Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with ... ...

Abstract	Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript. Direct sequencing of this gene in two siblings from another consanguineous family affected by isolated KFS uncovered another homozygous truncating (nonsense) MEOX1 mutation that also leads to complete degradation of the transcript. This gene encodes a transcription factor with a well-established and nonredundant role in somite development, and homozygous null alleles of Meox1 in mice have a cervical skeletal defect that is remarkably similar to the one we observe in human individuals with MEOX1 mutations. Our data strongly suggest that KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.
MeSH term(s)	Child ; Female ; Genes, Recessive ; Homeodomain Proteins ; Humans ; Klippel-Feil Syndrome/genetics ; Male ; Mutation ; Transcription Factors/genetics
Chemical Substances	Homeodomain Proteins ; MEOX1 protein, human ; Transcription Factors
Language	English
Publishing date	2013-01-03
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2012.11.016
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Article ; Online: Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia.

Zahrani, Fatema / Aldahmesh, Mohammed A / Alshammari, Muneera J / Al-Hazzaa, Selwa A F / Alkuraya, Fowzan S

American journal of human genetics

2013 Volume 92, Issue 3, Page(s) 387–391

Abstract: Microphthalmia is an important developmental eye disorder. Although mutations in several genes have been linked to this condition, they only account for a minority of cases. We performed autozygome analysis and exome sequencing on a multiplex ... ...

Abstract	Microphthalmia is an important developmental eye disorder. Although mutations in several genes have been linked to this condition, they only account for a minority of cases. We performed autozygome analysis and exome sequencing on a multiplex consanguineous family in which colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities, and we identified a homozygous truncating mutation in C12orf57 [c.1A>G; p.Met1?]. In a simplex case with a similar phenotype, we identified compound heterozygosity for the same mutation and another missense mutation [c.152T>A; p.Leu51Gln]. Little is known about C12orf57 but we show that it is expressed in several mouse tissues, including the eye and brain. Our data strongly implicate mutations in C12orf57 in the pathogenesis of a clinically distinct autosomal-recessive syndromic form of colobomatous microphthalmia.
MeSH term(s)	Adolescent ; Animals ; Brain Diseases, Metabolic, Inborn/genetics ; Child ; Child, Preschool ; Coloboma/genetics ; Corneal Opacity/genetics ; Exome ; Eye/metabolism ; Female ; Genetic Predisposition to Disease ; Heterozygote ; Homozygote ; Humans ; Intellectual Disability/genetics ; Male ; Mice ; Microcephaly/genetics ; Microphthalmos/genetics ; Mutation ; Phenotype ; Young Adult
Language	English
Publishing date	2013-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2013.01.008
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Article ; Online: Weaver syndrome and defective cortical development: a rare association.

Al-Salem, Ahmed / Alshammari, Muneera J / Hassan, Hamdy / Alazami, Anas M / Alkuraya, Fowzan S

American journal of medical genetics. Part A

2012 Volume 161A, Issue 1, Page(s) 225–227

MeSH term(s)	Abnormalities, Multiple/diagnosis ; Abnormalities, Multiple/genetics ; Congenital Hypothyroidism/diagnosis ; Congenital Hypothyroidism/genetics ; Craniofacial Abnormalities/diagnosis ; Craniofacial Abnormalities/genetics ; Enhancer of Zeste Homolog 2 Protein ; Exons ; Hand Deformities, Congenital/diagnosis ; Hand Deformities, Congenital/genetics ; Humans ; Infant ; Male ; Mutation ; Polycomb Repressive Complex 2/genetics
Chemical Substances	EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
Language	English
Publishing date	2012-12-13
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.35660
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Article ; Online: A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency.

Shaheen, Ranad / Ansari, Shinu / Alshammari, Muneera J / Alkhalidi, Hisham / Alrukban, Hadeel / Eyaid, Wafaa / Alkuraya, Fowzan S

Journal of medical genetics

2013 Volume 50, Issue 7, Page(s) 431–436

Abstract: Background: Numerous syndromic forms of intellectual disability have been described including those with abnormal sweating pattern.: Purpose: To describe the clinical and molecular analysis of a large multiplex consanguineous Saudi family with an ... ...

Abstract	Background: Numerous syndromic forms of intellectual disability have been described including those with abnormal sweating pattern. Purpose: To describe the clinical and molecular analysis of a large multiplex consanguineous Saudi family with an unusual constellation of severe intellectual disability, hypohidrosis, abnormal teeth, and acquired microcephaly. Methods: Clinical evaluation, autozygosity mapping, exome sequencing, and expression analysis. Results: Autozygosity mapping revealed a single critical locus corresponding to chr13:39 338 062-40 857 430. Exome sequencing uncovered a deep intronic (NM_020751.2:c.1167-24A>G) variant in COG6 that largely replaces the consensus acceptor site, resulting in pronounced reduction of the normal transcript and consequent deficiency of COG6 protein. Patient cells also exhibited pronounced deficiency of STX6, consistent with the established stabilising effect of COG6 on STX6. Four additional patients representing two families of the same tribal origin as the original family were found to have the same mutation, confirming a founder effect. Remarkably, none of the patients displayed any detectable abnormality in the glycosylation pattern of transferrin, which contradicts a previously published report of a patient whose abnormal glycosylation pattern was presumed to be caused by a missense variant in COG6. Conclusions: Our data implicate COG6 in the pathogenesis of a novel hypohidrotic disorder in humans that is distinct from congenital disorders of glycosylation.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/deficiency ; Adaptor Proteins, Vesicular Transport/genetics ; Base Sequence ; Child ; Consanguinity ; Glycosylation ; Humans ; Hypohidrosis/genetics ; Intellectual Disability/genetics ; Male ; Molecular Sequence Data ; Pedigree ; Syndrome
Chemical Substances	Adaptor Proteins, Vesicular Transport ; COG6 protein, human
Language	English
Publishing date	2013-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2013-101527
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Article ; Online: The syndrome of microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is caused by mutations in ADAMTS18.

Aldahmesh, Mohammed A / Alshammari, Muneera J / Khan, Arif O / Mohamed, Jawahir Y / Alhabib, Fatimah A / Alkuraya, Fowzan S

Human mutation

2013 Volume 34, Issue 9, Page(s) 1195–1199

Abstract: One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the ... ...

Abstract	One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18. Direct sequencing of this gene in four additional probands with the same phenotype revealed three additional homozygous changes in ADAMTS18 including two nonsense mutations. Reassuringly, the autozygomes of all probands overlap on the same chr16q23.1 locus, further supporting the positional mapping of MMCAT to ADAMTS18. ADAMTS18 encodes a member of a family of metalloproteinases that are known for their role in extracellular matrix remodeling, and previous work has shown a strong expression of Adamts18 in the developing eye. Our data suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and myopia.
MeSH term(s)	ADAM Proteins/genetics ; ADAMTS Proteins ; Amino Acid Sequence ; Child ; Chromosomes, Human, Pair 6 ; Codon, Nonsense ; Cornea/abnormalities ; Cornea/pathology ; Corneal Dystrophies, Hereditary/genetics ; Craniofacial Abnormalities/genetics ; Exome ; Eye Abnormalities/genetics ; Eye Abnormalities/physiopathology ; Eye Diseases, Hereditary/genetics ; Eye Diseases, Hereditary/physiopathology ; Humans ; Molecular Sequence Data ; Mutation, Missense ; Myopia, Degenerative/genetics ; Pedigree ; Phenotype ; Phylogeny ; Saudi Arabia ; Sequence Analysis, DNA
Chemical Substances	Codon, Nonsense ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS Proteins (EC 3.4.24.-) ; ADAMTS18 protein, human (EC 3.4.24.-)
Language	English
Publishing date	2013-09
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.22374
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Article ; Online: Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation.

Shaheen, Ranad / Alazami, Anas M / Alshammari, Muneera J / Faqeih, Eissa / Alhashmi, Nadia / Mousa, Noon / Alsinani, Aisha / Ansari, Shinu / Alzahrani, Fatema / Al-Owain, Mohammed / Alzayed, Zayed S / Alkuraya, Fowzan S

Journal of medical genetics

2012 Volume 49, Issue 10, Page(s) 630–635

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Arabia ; Base Sequence ; Collagen Type I/genetics ; Consanguinity ; Exons ; Female ; Gene Order ; Genes, Recessive ; Homozygote ; Humans ; Infant ; Infant, Newborn ; Ion Channels/genetics ; Male ; Mutation ; Osteogenesis Imperfecta/diagnosis ; Osteogenesis Imperfecta/genetics
Chemical Substances	Collagen Type I ; Ion Channels ; TMEM38B protein, human ; alpha 2(I) collagen ; collagen type I, alpha 1 chain
Language	English
Publishing date	2012-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2012-101142
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