Table 1.
List of Candidate Genes with More Than One Mutational Event Identified in this Cohort
| ID | Gene | Variant(s) | Zygosity | Phenotype | Justification |
|---|---|---|---|---|---|
| 17-1192 | ALKBH8 | GenBank: NM_001301010.1:c.1660C>T:p.Arg554Ter | Hom | Nonspecific intellectual disability with positive family history | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (this gene is involved in tRNA modification, a process that is increasingly recognized as the core feature of a number of intellectual disability syndromes, most notoriously ADAT3-related, which is one of the most common forms of intellectual disability in Arabia). |
| 17-6071 | ALKBH8 | GenBank: NM_001301010.1:c.1794delC:p.Trp599GlyfsTer19 | Hom | Nonspecific intellectual disability with positive family history | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (this gene is involved in tRNA modification, a process that is increasingly recognized as the core feature of a number of intellectual disability syndromes, most notoriously ADAT3-related, which is one of the most common forms of intellectual disability in Arabia). |
| 17-1025 | EIF2A | GenBank: NM_032025.4:c.649_650insT:p.Ser217MetfsTer4 | Hom | Intellectual disability, ASD, and epilepsy | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene. This gene encodes a eukaryotic translation initiation factor that functions in the early steps of protein synthesis of a small number of specific mRNAs and is used for initiation at non-AUG codons (see PMID: 28982758). |
| 17-6950 | EIF2A | GenBank: NM_032025.4:c.1229A>C:p.Gln410Pro | Hom | Intellectual disability and intractable epilepsy | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene. This gene encodes a eukaryotic translation initiation factor that functions in the early steps of protein synthesis of a small number of specific mRNAs and is used for initiation at non-AUG codons (see PMID: 28982758). |
| 18-2383 | ICE1 | GenBank: NM_015325.2:c.3724G>T:p.Asp1242Tyr | Hom | GDD, spasticity, optic atrophy, and brain atrophy | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (ICE1 promotes a link between splicing and nonsense-mediated mRNA decay [NMD]. Mutations in other NMD-related genes result in neurodevelopmental disorders. See PMID: 29528287). |
| REQ18-0816 | ICE1 | GenBank: NM_015325.2:c.603A>C:p.Lys201Asn | Hom | GDD and nonspecific brain atrophy | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (ICE1 promotes a link between splicing and nonsense-mediated mRNA decay [NMD]. Mutations in other NMD-related genes result in neurodevelopmental disorders. See PMID: 29528287). |
| 17-5039 | IQSEC3 | GenBank: NM_015232.1:c.1144G>A:p.Gly382Ser | Hom | Speech delay, intellectual disability, ASD, and seizures (generalized tonic clonic) | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (IQSEC3 acts together with gephyrin to regulate inhibitory synapse development). |
| 17-5139 | IQSEC3 | GenBank: NM_001170738.1:c.3340C>A:p.Leu1114Met | Hom | Cognitive and speech delay | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (IQSEC3 acts together with gephyrin to regulate inhibitory synapse development). |
| 17-0049-C | MOV10 | GenBank: NM_001130079.2:c.2101_2102insA:p.Ser701TyrfsTer18 | Het | Gross motor delay, IUGR, oligohydramnios, hepatosplenomegaly, and cholestasis | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.99). Mov10 is a novel telomerase-associated protein (see PMID: 19665004). It was demonstrated that Mov10 is essential for gastrulation and for normal head, eye, and brain development (see PMID: 28662698). Consistent with the mouse model, knockdown of maternal Mov10 in Xenopus led to defects in gastrulation and the development of notochord and paraxial mesoderm and a failure to neurulate (see PMID: 29266590). |
| 18-1423 | MOV10 | GenBank: NM_001130079.2:c.2268_2269insTCGTGGA:p.Val757SerfsTer32 | Het | Large patent ductus arteriosus, scoliosis, hemivertebrae, phocomelia, and omphalocele versus gastroschisis | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.99). Mov10 is a novel telomerase-associated protein (see PMID: 19665004). It was demonstrated that Mov10 is essential for gastrulation and for normal head, eye, and brain development (see PMID: 28662698). Consistent with the mouse model, knockdown of maternal Mov10 in Xenopus led to defects in gastrulation and the development of notochord and paraxial mesoderm and a failure to neurulate (see PMID: 29266590). |
| 17-2799 | PLXNA3 | GenBank: NM_017514.5:c.1997G>A:p.Arg666His | Hemi | Epilepsy (generalized absence seizures), mild memory deficits, and history of IUGR during pregnancy | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.98. It was demonstrated that Plexin A3 is involved in semaphorin 3F-mediated oligodendrocyte precursor cell migration (see PMID: 23063687), contributes to Sema3F and Sema3A signaling, regulates the development of hippocampal axonal projections in vivo (see PMID: 11683995), mediates neuronal apoptosis during dorsal root ganglia development (see PMID: 19020035), and regulates motor axonal branch morphogenesis (see PMID: 23349787). |
| 18-1411 | PLXNA3 | GenBank: NM_017514.5:c.2623C>T:p.Arg875Trp | Hemi | Intellectual disability, autistic features, and has a twin (18-1631) with same condition | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.98). It was demonstrated that Plexin A3 is involved in semaphorin 3F-mediated oligodendrocyte precursor cell migration (see PMID: 23063687), contributes to Sema3F and Sema3A signaling, regulates the development of hippocampal axonal projections in vivo (see PMID: 11683995), mediates neuronal apoptosis during dorsal root ganglia development (see PMID: 19020035), and regulates motor axonal branch morphogenesis (see PMID: 23349787). |
| 17-6562 | PTPN12 | GenBank: NM_001131009.1:c.722C>A:p.Pro241His | Het | GDD, failure to thrive, microcephaly, and epilepsy | (1) The nature of the variant (predicted deleterious in silico) and (2) the nature of the gene (pLI 0.99). Mutations in other family members, e.g., PTPN23 and PTPN11, are identified in individuals with intellectual disability and other neurodevelopmental disorders (see PMID: 25558065, PMID: 29090338, and PMID: 28957739). |
| 17-8496 | PTPN12 | GenBank: NM_002835.3:c.2282-34A>T | Hom | GDD and nonspecific MRI findings | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (pLI 0.99). Mutations in other family members, e.g., PTPN23 and PTPN11, are identified in individuals with intellectual disability and other neurodevelopmental disorders (see PMID: 25558065, PMID: 29090338, and PMID: 28957739). |
| 18-0081 | RASIP1 | GenBank: NM_017805.2:c.2325G>C:p.Leu775Phe | Het | Microcephaly and fibular hemimelia | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.97). RASIP1 is a dynamic EPAC1-RAP1 signaling effector that controls actin bundling and restricts junction remodeling in vitro and in vivo, and it is required for stabilizing nascent patent blood vessels in both mice and zebrafish (see PMID: 23886837). It was reported that the distribution of the intersegmental arteries plays a decisive role in the formation of the definitive vertebral body anlage during the stage of resegmentation and early chondrification, and any abnormal distribution of the arteries might induce malformations (see PMID: 6797230). |
| REQ18-1889 | RASIP1 | GenBank: NM_017805.2:c.1193_1196delATGT:p.Tyr398Ter | Het | Butterfly vertebrae, bilateral fused ribs, and diaphragmatic anomaly | (1) The nature of the variant (predicted deleterious) and (2) the nature of the gene (PLI: 0.97). RASIP1 is a dynamic EPAC1-RAP1 signaling effector of that controls actin bundling and restricts junction remodeling in vitro and in vivo, and it is required for stabilizing nascent patent blood vessels in both mice and zebrafish (see PMID: 23886837). It was reported that the distribution of the intersegmental arteries plays a decisive role in the formation of the definitive vertebral body anlage during the stage of resegmentation and early chondrification and any abnormal distribution of the arteries might induce malformations (see PMID: 6797230). |
| 17-5563 | SMG8 | GenBank: NM_018149.6:c.623A>G:p.His208Arg | Hom | Microcephaly, intellectual disability, cataract, and neck hyperpigmentation | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (this is a nonsense-mediated mRNA decay factor). Mutations in the NMD complex have been shown to result in multisystem involvement (PMID: 27018474). Recessive inheritance was confirmed by parental (17-5564 and 17-5565) whole-exome sequencing. An affected sibling (17-5566) is also homozygous for this variant. |
| REQ18-0840 | SMG8 | GenBank: NM_018149.6:c.437_438insA:p.Ser146ArgfsTer13 | Hom | Growth retardation and/or short stature, microcephaly, fine motor delay, ventricular septal defect, failure to thrive, and facial dysmorphism | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (this is a nonsense-mediated mRNA decay factor). Mutations in the NMD complex have been shown to result in multisystem involvement (PMID: 27018474). |
| 17-3980 | SMPD4 | GenBank: NM_001171083.2:c.1471-28_1477del | Hom | Bilateral clenched hands and talipes, IUGR, partial absence of corpus callosum, and family history of three neonatal deaths with similar features | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) SMPD4, a bona fide sphingomyelinase in the ceramide pathway, catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide (PMID: 16517606). Interestingly, inactivation or knockout of another sphingomyelinase of the ceramide pathway, SMPD3, led to growth inhibition, apoptosis, retarded development, and ultimately to a lethal, autosomal-recessive form of osteogenesis imperfecta, skeletal malformations, dwarfism, and severe chondrodysplasia as a result of the deficient sphingomyelinase activity (PMID: 16025116 and PMID: 27882938). |
| 17-6035 | SMPD4 | GenBank: NM_017751.4:c.390_406del:p.Pro131LeufsTer2 | Hom | Failure to thrive, fine and gross motor delay, brain atrophy, syndactyly, hypoplasia of phalanges, and short metacarpal bones | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) SMPD4, a bona fide sphingomyelinase in the ceramide pathway, catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide (PMID: 16517606). Interestingly, inactivation or knockout of another sphingomyelinase of the ceramide pathway, SMPD3, led to growth inhibition, apoptosis, retarded development, and ultimately to a lethal, autosomal-recessive form of osteogenesis imperfecta, skeletal malformations, dwarfism, and severe chondrodysplasia as a result of the deficient sphingomyelinase activity (PMID: 16025116 and PMID: 27882938). |
| 17-4956 | TP73 | GenBank: NM_001126242.2:c.1163delT:p.Leu388HisfsTer151 | Hom | Lissencephaly and hypotonia | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the loss of p73 leads to the disappearance of the Cajal-Retzius (CR) neurons in the cortical marginal zone and hippocampal molecular layer, and this could underlie the hippocampal dysgenesis, the hydrocephalus, and the abnormalities in the pheromone sensory pathways in p73 mice (PMID: 10716451). |
| 17-6638 | TP73 | GenBank: NM_001126240.2:c.847C>T:p.Gln283Ter | Hom | Fine and gross motor delay, speech delay, cleft lip and/or palate, cortical dysplasia, pachygyria, and strabismus | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the loss of p73 leads to the disappearance of the Cajal-Retzius (CR) neurons in the cortical marginal zone and hippocampal molecular layer, and this could underlie the hippocampal dysgenesis, the hydrocephalus, and the abnormalities in the pheromone sensory pathways in p73 mice (PMID: 10716451). |
| 17-6690 | UNC5A | GenBank: NM_133369.2:c.1309C>T:p.Arg437Ter | Hom | Failure to thrive, microcephaly, GDD, hearing loss, periventricular leukomalacia, and seizures | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene (UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains) guides cell and pioneer axon migrations in C. elegans (see PMID: 1384987). |
| 17-7961 | UNC5A | GenBank: NM_133369.2:c.1550T>A:p.Ile517Asn | Hom | Congenital heart disease, failure to thrive, microcephaly, GDD, nystagmus, cafe au lait spots, and seizures. | (1) The nature of the variant (predicted deleterious, within autozygome) and (2) the nature of the gene: UNC5A belongs to a family of netrin-1 receptors thought to mediate the chemo repulsive effect of netrin-1 on specific axons (see PMID: 1384987). A loss-of-function variant of UNC5A is identified in an individual with failure to thrive, microcephaly, GDD, hearing loss, periventricular leukomalacia, and seizures (see 17-6690). |
| 17-2828-B | USO1 | GenBank: NM_003715.3:c.46G46G>C:p.Val16LeuVal161Leu | Hom | Developmental regression, retinal degeneration, and suspected NCL | (1) The nature of the variant (present within autozygome, predicted deleterious in silico) and (2) the nature of the gene: USO1, a vesicle transport factor, is a peripheral membrane protein that recycles between the cytosol and the Golgi apparatus. Mice lacking USO1 exhibit disruption of Golgi structure and early embryonic lethality (see PMID: 23185636 and MGI: 1929095). |
| 17-6599 | USO1 | GenBank: NM_003715.3:c.46G46G>C:p.Val16LeuVal161Leu | Hom | Developmental regression, retinal degeneration, and suspected NCL | (1) The nature of the variant (present within autozygome, predicted deleterious in silico) and (2) the nature of the gene: USO1, a vesicle transport factor, is a peripheral membrane protein that recycles between the cytosol and the Golgi apparatus. Mice lacking USO1 exhibit disruption of Golgi structure and early embryonic lethality (see PMID: 23185636 and MGI: 1929095). |
| 17-8522 | USO1 | GenBank: NM_003715.3:c.2514T>G:p.Ile739Arg | Hom | GDD, microcephaly, epilepsy, optic atrophy, and suspected NCL | (1) The nature of the variant (present within autozygome, predicted deleterious in silico) and (2) the nature of the gene: USO1, a vesicle transport factor, is a peripheral membrane protein that recycles between the cytosol and the Golgi apparatus. Mice lacking USO1 exhibit disruption of Golgi structure and early embryonic lethality (see PMID: 23185636 and MGI: 1929095). |
Abbreviations are as follows: Hom = homozygous, Het = heterozygous, Hemi = hemizygous, IUGR = intrauterine growth restriction, MRI = magnetic resonance imaging, NCL = neuronal ceroid lipofuscinosis, and GDD = global developmental delay