Table 1 Candidate Genes. Several were published previously through gene matching.
Family-ID | Index's Age at exome test | Index's Gender | Other Affected | Phenotype | Gene-Approved | HGVS variant (hg19) | Zygosity | Consanguinity | avsnp150 rs | GnomAD frequency | Pathogenicity Scores * | Function & experimental models | Remarks |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
11SS10900 | 2 Years | Female | No | Refractory seizures and developmental delay | AATK | AATK(NM_001080395.3):c.533 + 1G > A (p.?) | homozygous | Yes | NA | Absent | NA | Apoptosis-associated tyrosine kinase (AATK) is a non-receptor type tyrosine kinase whose expression is up-regulated during the apoptosis and differentiation of 32Dcl3 myeloblastic cells. AATK plays an essential role in mature neurons and neuronal differentiation40,41 | No published genotype–phenotype association |
10DK8100 | 12 Years | Male | Yes | Autistic features, intellectual disability, hyperactivity, and normal MRI brain | AP1G2 | AP1G2(NM_003917.5):c.2269C > A (p.Leu757Ile) | homozygous | Yes | rs764435650 | 0.0000319 | 0/4 | The AP1G2 gene encodes gamma-2-adaptin, a protein very similar to gamma-adaptin (AP1G1), a subunit of the AP1 adaptor complex that engages clathrin to the trans-Golgi network. It might have a role in protein sorting in late endosomes or multivesicular bodies42. Zebrafish whole-mount in situ hybridization confirmed that γ2 adaptin (encoded by AP1G2) is detected in the developing central nervous system (CNS) and knockout in zebrafish embryos showed severe, lethal impairment of CNS development43. The partner protein AP1G1 was recently published to cause ID44 | No published genotype–phenotype association |
12DK11500 | 11 Years | Male | Yes | Facial dysmorphic features, severe neurodevelopmental delay, cortical visual impairment and seizures | CAMSAP1 | CAMSAP1(NM_015447.4):c.521C > T (p.Thr174Met) | homozygous | Yes | rs1187560194 | 0.0000319 | 1/4 | CAMSAP1 is a microtubule-organizing protein that binds to the minus end of non-centrosomal microtubules and regulates their dynamics and organization45. It is involved in other processes, including neuron projection development and regulation of cell morphogenesis46 | Gene Matched (understudy) |
10BS15400 | 1 Year | Male | Yes | Severe intellectual disability, seizures, face dysmorphism, hypopigmented hair and skin | CCDC9B | CCDC9B(NM_207380.2):c.796_815del (p.Leu266AlafsTer35) | homozygous | Yes | NA | Absent | NA | CCDC9B (C15orf52) is expressed in the brain. Mouse KO data indicated a neurological phenotype. It showed decreased exploration in new environments and decreased prepulse inhibition (MGI:2685199) | No published genotype–phenotype association |
10DH6800 | 14 Years | Female | Yes | Short stature, microcephaly, cataract, abnormal teeth, obesity, hypertension, and insulin resistance | CNTROB | CNTROB(NM_001037144.7):c.355 + 1G > A (p.?) | homozygous | Yes | rs752440318 | 7.95E-06 | NA | CNTROB is a centrosomal protein involved in centriole duplication and cytokinesis47. It is expressed in the brain. It was observed that inhibiting centriole duplication causes cytokinesis defects. In mice, In hippocampal cells, centrobin formed cytoplasmic dots. It enhanced microtubule formation outside as well as inside the centrosome | Gene Matched (understudy) |
10SS7900 | 7 Years | Male | Yes | Intellectual disability | DNAH14 | DNAH14(NM_001367479.1):c.5716A > C (p.Lys1906Gln) | homozygous | Yes | rs868380191 | Absent | 4/4 | DNAH14 encodes a microtubule-associated motor protein that contributes to centrosome integrity. DNAH14 was found to be a causative gene in patients with hydrocephalus. Since DNAH14 encodes axonemal dynein, which is found in motile cilia it is believed to affect cilia physiological function during hydrocephalus pathogenesis48. Mutation in DNAH14 was also linked to human embryonic lethality49 | One study was published recently with no further confirmation50, and no associated OMIM phenotype entry |
10SN8700 | 6 Years | Male | Yes | IUGR, recurrent pneumonia (lipoid), ventilator-dependent, inguinal hernia, thin corpus callosum and mild to moderate brain atrophy | DNAJB4 | DNAJB4(NM_007034.5):c.181A > G (p.Arg61Gly) | homozygous | Yes | NA | Absent | 4/4 | DNAJB4 is a member of the highly conserved DNAJ/HSP40 protein family. It functions as a chaperone for E-cadherin, allowing appropriate folding, localization, and stability, implying a post-transcriptional level of control51. DNAJB4 binds to the carboxyl tail of the human mu opioid receptor in the CNS52. DNAJB4 was found to interact with SDIM1, which is thought to play a particular role in brain cell survival and/or receptor trafficking53 | No published genotype–phenotype association |
30DF4200 | 12 Years | Female | Yes | Intellectual disability, microcephaly, facial dysmorphism, microphthalmia and eczema | DRG1 | DRG1(NM_004147.4):c.160G > T (p.Gly54Ter) | homozygous | Yes | NA | Absent | NA | DRG1 is a microtubule-binding protein that performs various microtubule-related functions54. Based on its expression pattern, DRG1 may be involved in neuronal cell proliferation and/or differentiation55. DRG1 transcript levels in the developing central nervous system of Xenopus laevis revealed a similar pattern of expression56 | Gene Matched (understudy) |
10BN7700 | 7 Years | Male | Yes | Normocephalic, global developmental delay, and spastic paraplegia | DTNBP1 | DTNBP1(NM_032122.5):c.811 + 6G > A (p.?) | homozygous | Yes | NA | Absent | NA | Dysbindin protein is a significant component of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), which controls protein trafficking in the lysosomal pathway57. DTNBP1 has been identified to have a role in the development of schizophrenia by affecting brain development and neurotransmission activity58 | Studies associated DTNBP1 variants with schizophrenia with no further functional confirmation59 |
10DK15000 | 12 Years | Female | Yes | Intellectual disability | EDRF1 | EDRF1(NM_001202438.2):c.2591-1G > A (p.?) | homozygous | Yes | NA | Absent | NA | EDRF1 is a transcription factor60; it is highly expressed in the brain | No published genotype–phenotype association |
10BS10700 | 7 Years | Female | Yes | Global developmental delay, microcephaly, severe visual impairment hypomyelination and hypoplastic corpus callosum | EEF1D | EEF1D(NM_001130053.4):c.1905 + 1G > A (p.?) | homozygous | Yes | rs1364060781 | 3.99E-06 | NA | EEF1D gene encodes three different splice forms proteins in addition to a more recently described isoform called eEF1BδL that functions during cellular stress as a transcription factor for heat shock element-containing genes61. Mutations in the EEF1D gene have been associated with neurodevelopmental abnormalities62 | Gene Matched (understudy) |
10MS2400 | 4 Years | Male | Yes | Severe acquired microcephaly, severe delay, seizures, optic nerve atrophy, and hypotonia | EXOC8 | EXOC8(NM_175876.5):c.692A > G (p.Tyr231Cys) | homozygous | Yes | rs1558358137 | Absent | 4/4 | EXOC8 is a subunit of the exocyst complex involved in docking exocytic vesicles with fusion sites on the plasma membrane. It is found to play an essential role in normal cortical development and its perturbation causes complex brain disorders. EXOC8 mutations (one family) are linked to neurodevelopmental disorders with microcephaly, seizures, and brain atrophy63 | ?Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy (MIM# 619,076), Two studies correlated EXOC8 variants with a neurodevelopmental phenotype63,64, functional studies of the variant and studies of patient cells were not performed |
10DF16100 | 14 Years | Female | Yes | Prenatal growth restrictions, failure to thrive, short stature, global developmental delay, intracerebral calcification and basal ganglia calcifications, and kidney failure | EXOSC4 | EXOSC4(NM_019037.3):c.560 T > C (p.Leu187Pro) | homozygous | Yes | NA | Absent | 2/4 | EXOSC4 is a non-catalytic component of the RNA exosome complex with 3'- > 5' exoribonuclease activity and involvement in numerous cellular RNA processing and degradation events65. EXOSC4 is involved in the nucleic acid metabolic process and positive regulation of cell growth66. Mutations in other 3'- > 5' exoribonucleases enzymes were associated with a neurodevelopmental disorder67,68 | Gene Matched (understudy) |
10DH13900 | 28 Years | Female | Yes | Brain calcification, microcephaly, short stature and lung disease | FARSB | FARSB(NM_005687.5):c.853G > A (p.Glu285Lys) | homozygous | Yes | rs767956337 | Absent | 1/4 | Cytoplasmic phenylalanine-tRNA synthetase is a heterodimer composed of a catalytic alpha subunit, FARSA, and a regulatory beta subunit, FARSB. FARSB is an aminoacyl-tRNA synthetase that charges tRNAs with specific amino acids. It is reported to be associated with neurodevelopmental disorders69,70 | Published69 |
30BN13200 | 3 Years | Male | Yes | Symmetrical IUGR, clenched hands, hypertelorism, generalized hypotonia, duodenal atresia and annular pancreas | FBXO22 | FBXO22(NM_012170.3):c.159_162del (p.Arg53SerfsTer13) | homozygous | Yes | NA | Absent | NA | FBXO22 is a Member of the F-box protein family, which is characterized by comprising 40-amino acid F-box domain. F-box proteins form complexes with other proteins and act as protein-ubiquitin ligases. FBXO22 plays a critical in carcinogenesis and may participate in the progression of parkinsonism71,72 | Gene Matched (understudy) |
10MS16500 | 1 Years | Male | Yes | Distal arthrogryposis with contractures of the knees and elbows, congenital clubfoot, muscular hypotonia, and mild learning disability | FILIP1 | FILIP1(NM_015687.5):c.2665C > T (p.Arg889Ter) | homozygous | Yes | rs775141616 | 1.19E-05 | NA | FILIP1 regulates the migration of neocortical cells from the ventricular zone by acting via a filamin-A/F-actin axis. It may cause filamin-A degradation73,74 | Gene Matched (understudy) |
10DK16000 | 8 Months | Female | Yes | Severe Global developmental delay and pontocerebellar hypoplasia | INPP4A | INPP4A(NM_001134224.1):c.2702G > C (p.Arg901Pro) | homozygous | Yes | NA | Absent | 4/4 | INPP4A catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, as well as inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate75. INPP4A-null mice developed neurodegeneration in the striatum and severe involuntary movement disorders (MGI:1,931,123) | One study identified a novel nonsense INPP4A mutation in a family with intellectual disability76, with no further functional confirmation and no associated OMIM phenotype entry |
10DH9400 | 11 Years | Female | Yes | Global developmental delay, seizures, and visual problems | P2RX7 | P2RX7(NM_002562.6):c.614C > T (p.Thr205Met) | homozygous | Yes | rs140915863 | 0.000127 | 0/4 | P2RX7 is an ATP receptor that functions as a ligand-gated ion channel. When its native ligand, ATP, is not present, it acts as a scavenger receptor, recognizing and engulfing apoptotic cells (Ivetac et al., 2005). It is responsible for the ATP-dependent lysis of macrophages77. It can potentially participate in both rapid synaptic transmission and ATP-mediated lysis of antigen-presenting cells. P2X7R was found to have roles in neuroinflammation and implications in Alzheimer's disease pathogenesis78 | No published genotype–phenotype association |
10DK3900 | 2 Years | Male | No | Central hypoventilation and apnea, seizures, cerebellar vermis hypoplasia and early death | PRDM13 | PRDM13(NM_021620.4):c.800del (p.Gly267AspfsTer34) | homozygous | Yes | NA | Absent | NA | PRDM13 is implicated in transcriptional regulation. It is thought to be a vital component of a highly coordinated transcriptional network that determines the balance of inhibitory versus excitatory neurons in the dorsal spinal cord79 | Published80 |
10MS13800 | 11 Years | Female | Yes | Global developmental delay, extrapyramidal features and spasticity | PTRHD1 | PTRHD1(NM_001013663.2):c.169_196del (p.Ala57ArgfsTer26) | homozygous | Yes | rs553276736 | 0.000541 | NA | Putative peptidyl-tRNA hydrolase with a PTH2 domain, implying that it works in the ubiquitin–proteasome pathway. It was suggested to be linked to early-onset parkinsonism and cognitive dysfunction81,82 | Published83 |
10SS5400 | 4 Years | Male | Yes | Hypotonia, global developmental delay, and seizures. Parents are healthy | SCN10A; CDC42BPB | SCN10A(NM_001293307.2):c.3916 T > G (p.Phe1306Val);CDC42BPB(NM_006035.4):c.3941del (p.Ala1314GlyfsTer35) | homozygous; homozygous | Yes | NA; NA | Absent; Absent | 4/4; NA | SCN10A gene encodes the alpha subunit of a voltage-gated sodium channel, an integral membrane glycoprotein responsible for the initial rising phase of action in most excitable cells84; CDC42BPB encodes a Serine/threonine-protein kinase that is an important downstream effector of CDC42 and regulates cytoskeleton reorganization and cell migration. Recently loss-of-function variants in this gene were associated with a neurodevelopmental phenotype85 | SCN10A: one study published as a cause of ID with no further confirmation and no associated OMIM entry86, other associated disease is an episodic pain syndrome; CDC42BPB: one study published only describing de novo mutations (autosomal dominate) with no further confirmation85. OMIM phenotype: Chilton-Okur-Chung neurodevelopmental syndrome (MIM# 619,841). No biallelic variants for CDC42BPB described |
14MS2200 | 2 Years | Female | Yes | Arthrogryposis, global developmental delay, microcephaly, and optic disc pallor | SCYL2 | SCYL2(NM_017988.6):c.1624dup (p.Val542GlyfsTer16) | homozygous | Yes | NA | Absent | NA | SCYL2 regulates the production of excitatory receptors at synapses and plays an essential role in regulating neuronal function, signaling, and brain development87. Mutations in this gene have been linked to neurogenic arthrogryposis multiplex congenita-4 with corpus callosum agenesis (MIM# 618,766) | Published88 |
10DF10800 | 5 Years | Male | Yes | Global developmental delay with severely impaired intellectual function and absent speech, additionally Usher syndrome phenotype | SMG8 | SMG8(NM_018149.6):c.1121_1122insG (p.Gly375TrpfsTer3); USH1G(NM_173477.5):c.1286_1295dup (p.Leu433GlnfsTer109) | homozygous | Yes | NA; NA | Absent; Absent | NA; NA | SMG8 gene encodes a component of the cell's nonsense-mediated mRNA decay (NMD) machinery. SMG8 and SMG9 as partners regulate the kinase activity of SMG1 | Published39 |
10BS16700 | 5 Years | Male | No | Severe intellectual disability, spastic quadriparesis, axial hypotonia, abnormal brain MRI, and retinal dystrophy | SUPV3L1 | SUPV3L1(NM_003171.5):c.2215C > T (p.Gln739Ter) | homozygous | Yes | NA | Absent | NA | SUPV3L1 encodes a helicase that is localized in the mitochondria. It has been shown in vitro to possess both double-stranded RNA and DNA unwinding activity that is ATP-dependent | Gene Matched (understudy). One study was published recently with no further confirmation89 |
10DK16600 | 12 Years | Female | No | Intellectual disability, spastic quadriparesis, abnormal brain MRI, neuroregression, seizures, and optic neuropathy | SUPV3L1 | SUPV3L1(NM_003171.5):c.2215C > T (p.Gln739Ter) | homozygous | Yes | NA | Absent | NA | SUPV3L1 encodes a helicase that is localized in the mitochondria. It has been shown in vitro to possess both double-stranded RNA and DNA unwinding activity that is ATP-dependent | Gene Matched (understudy). One study was published recently with no further confirmation89 |
10BN7500 | 13 Years | Male | Yes | Intellectual disability | TACC2 | TACC2(NM_206862.4):c.8260G > A (p.Ala2754Thr) | homozygous | Yes | rs538968585 | 0.00002 | 0/4 | TACC2 is involved in the microtubule-dependent coupling of the nucleus and the centrosome and in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors90. TACC2 is a tumor suppressor and an oncogenic protein91 | No published genotype–phenotype association |
10SS8000 | 7 Years | Male | Yes | Moderate to severe intellectual deficiency, behavioral abnormalities, facial dysmorphism, and ophthalmological abnormalities | THUMPD1 | THUMPD1(NM_017736.5):c.774_776del (p.Leu258del) | homozygous | Yes | rs772419789 | 3.98E-06 | NA | THUMPD1 is highly expressed in the brain and it is a unique adaptor protein that regulates tRNA acetylation interacts through interaction with NAT1092 | Published93 |
10DK15900 | 2 Months | Female | Yes | Variable signs of cardiomyopathy, neonatal pulmonary hypertension, hypophosphatemia, chronic lung disease, developmental delay, and brain basal ganglia calcification | XPR1 | XPR1(NM_004736.4):c.1811G > A (p.Arg604Gln) | homozygous | Yes | NA | Absent | 4/4 | The XPR1 protein mediates phosphate export from the cell and binds inositol hexakisphosphate and related inositol polyphosphates, key intracellular signaling molecules. Mutations in XPR1 gene are associated with the dominant condition of idiopathic basal ganglia calcification-622,23. No ID phenotype in this condition | The patients' phenotype is strikingly different from the reported phentyope, with no past ID phenotype described. No biallelic variants for XPR1 were described |
10MS4500 | 4 Years | Female | Yes | Variable signs of cardiomyopathy, neonatal pulmonary hypertension, hypophosphatemia, chronic lung disease, developmental delay, and brain basal ganglia calcification | XPR1 | XPR1(NM_004736.4):c.1811G > A (p.Arg604Gln) | homozygous | Yes | NA | Absent | 4/4 | ||
50DK4600 | 2 Years | Male | Yes | Variable signs of cardiomyopathy, neonatal pulmonary hypertension, hypophosphatemia, chronic lung disease, developmental delay, and brain basal ganglia calcification | XPR1 | XPR1(NM_004736.4):c.1811G > A (p.Arg604Gln) | homozygous | Yes | NA | Absent | 4/4 | ||
63MS1200 | 3 Years | Male | Yes | Variable signs of cardiomyopathy, neonatal pulmonary hypertension, hypophosphatemia, chronic lung disease, developmental delay, and brain basal ganglia calcification | XPR1 | XPR1(NM_004736.4):c.1811G > A (p.Arg604Gln) | homozygous | Yes | NA | Absent | 4/4 | ||
22SN9300 | 6 Years | Female | Yes | Seizures and neurodegenerative disorder (? Leukodystrophy) in addition to also cystic fibrosis | ZFYVE28 | ZFYVE28(NM_020972.3):c.2015_2016del (p.Ser672CysfsTer67) | homozygous | Yes | NA | Absent | NA | ZFYVE28 has been found to operate as a negative regulator of epidermal growth factor receptor (EGFR) signaling. It promotes EGFR degradation in endosomes when not monoubiquitinated, thereby terminating EGFR signaling. The highest expression is seen in the brain at the cortex and cerebellum. These patients also have cystic fibrosis phenotype explained by CFTR pathogenic variants | No published genotype–phenotype association |
