1J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Malformations with Emphasis on Corpus Callosum Basmah Alomrani1, Murid Javed2, Hani S. H. Mohammed Ali 1,4*, Salah E. M. Abo-Aba1,4*, Albandary AlBakheet3, Hanan Alqudairy3, Namik Kaya3 1Department of Biological Science, King Abdul-Aziz University, Jeddah, Saudi Arabia. 2Originelle Fertility Clinic and Women’s Health Centre, Ottawa, Canada. 3Department of Genetics, King Faisal Specialists Hospital and Research Center, Riyadh, Saudi Arabia. 4Princess Dr. Najla Bent Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdul-Aziz University, Jeddah, Saudi Arabia. *Correspondence to: Hani S. H. Mohammed Ali (E-mail: hmohammedali@ksa.edu.sa); Salah E. M. Abo-Aba (E-mail: Salah_aboaba@yahoo.com) (Submitted: 11 December 2021 – Revised version received: 04 January 2022 – Accepted: 25 January 2022 – Published online: 26 February 2022) Abstract The pathological processes of the central nervous system, intrinsic or extrinsic, occurring during the embryonic period are the most common cause of pregnancy termination. The defects of the neural tube which is primitive form of brain and spinal cord are the most common central nervous system (CNS) malformations. In some defects the fetus continues to develop and results in the birth of a child with sever mental and physical deficiencies. The corpus callosum is the largest white matter tract connecting the two cerebral hemispheres and permits the transfer of information between the two cerebral hemispheres. Its partial or complete agenesis is caused by abnormalities during embryonic development. The severity of symptoms varies widely depending on the degree of dysgenesis. Hypotonia, visual impairment, seizures, spasticity, motor co-ordination issues, and atypical facial features are common symptoms. In this review we focus on genetic causes, clinical manifestations and diagnosis of various malformations of central nervous system with special emphasis on corpus callosum. Keywords: Central nervous system, corpus callosum, diagnosis ISSN 2413-0516 Introduction Malformations result from pathological processes occurring during the embryonic period. These pathological processes could be intrinsic or extrinsic. Fetal brain malformations occur at a rate of 2–3 per 1000 pregnancies and are considered the most common cause of pregnancy termination.1 The fetal brain begins to develop shortly after conception and continues to grow throughout pregnancy. The symptoms and prognosis of congenital brain malformations vary, depending on the type and severity. Neural tube defects (NTDs) are the most common central nervous system (CNS) malformations. The neural tube closure takes place at the fourth week post conception. The prevalence of NTDs at birth has decreased over the past few years due to the introduction of antenatal folic acid use, espe- cially during the 1st trimester.2 The brain develops from the cranial part (rostral part) of the neural tube. By the end of the fourth-week of gestation three primary cerebral vesicles are differentiated from the neural tube; namely the prosencephalon (forebrain), mesen- cephalon (midbrain), rhombencephalon (hindbrain).3 By the fifth week of gestation, the three primary vesicles further sub- divide into five secondary vesicles; telencephalon, that differ- entiates to the cerebral hemispheres; diencephalon, that differentiates to thalamus, hypothalamus, posterior pituitary and the optic vesicles; mesencephalon, that forms the mid- brain; metencephalon, that forms pons and cerebellum; and myelencephalon, that differentiates to medulla oblongata.4 Primary and secondary cerebral vesicles in early embryonic development are illustrated in Figure 1. Epigenetic and epigenomic focus on mechanisms gov- erning brain and behavior development, genetic evolution, neural resilience and homeostasis. Epigenetic studies tackle the etiology of neurological conditions in addition to normal neural processes.5 The four main epigenetic mechanisms involved in the dynamic identification of nuclear structure and genomic landscape are DNA methylation, chromatin modification, non-coding RNA editing of nuclear acids, and modification of histones. Environmental epigenomic science explores the environ- mental determinants that modulate the initiation and progres- sion of certain neurological conditions in addition to the identification of response of treatment interventions.6 Fur- thermore, pharmaco-epigenomics is a new science that is interested in therapies improving recovery of cognitive, behav- ioral, and senso-motor functions.7 DNA methylation is the most common mechanism which is catalyzed by DNA methyltransferase (DNMTs) that trans- fers a methyl group to DNA sequence and suppresses gene-transcription. A Similar RNA counterpart (DMT2) is responsible for gene-silencing in the developmental process. The DNA methylation shows interactions with various items of epigenetic machinery and contributes to the expression of epigenetic marks essential for multigenerational inheritance.9 Many studies found that individual-specific DNA methyl- ation is related to neuronal identity and specific functional development. The De novo methylation of DNA was found associated with the prevention of early premature develop- ment of stem cell neurons. Moreover, DNMT level is high in the nervous system of the embryo to preserve DNA methyla- tion during the division of neural precursors. Different forms of DNMT are found in the adult brain where they enhance brain cell repair and improve cell turnover. DNA methylation organizes the time of astrocyte development by mediating the mailto:hmohammedali@ksa.edu.sa mailto:Salah_aboaba@yahoo.com 2 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. methylenation of certain factors in the process of glial matura- tional genes.10 Epigenetics plays an important role in the identification of neural dysfunction associated with some conditions such as Rett Syndrome where the study of Mecp2 mutant mice pro- vides substantial insight into the pathological mechanisms of the syndrome.11 Dynamic remodeling of the chromatin network is medi- ated by many enzymes and signal transportation pathways. Chromatin is formed of DNA units with proteins, histone and non-histone, responsible for 3D folding of DNA and func- tional regulation of the nucleus. Furthermore, the nucleus contains molecular platforms for organizing genome-wide chromatin remodeling. Histone alteration and chromatin remodeling are related to neural stem cells repair which have been linked to many cognitive and behavioral disorders.12 In the eukaryotic nucleus, the areas of non-protein- coding have been remarkably increased, which reflected the functional development during evolution. However, the quan- tity of protein-coded areas has been unchanged. Human accel- erated genes (HARs) which are responsible for the evolution of humans from ancestors are identified in non-protein-coding regions of the genome, most of them adjacent to the essential neurodevelopmental genes. The most important genetic loci are HAR1, which is expressed with reelin, which participate in cortical neurons development.13 Two sub-types of RNA editing enzymes can modify the magnitude of expression and the functional differentiation of RNA. During neural development, RNA editing enzyme expressed changing subcellular localization within neurolog- ical development. The RNA editing can change biogenesis, maturation properties, immense gene products which play a broad variety of neurodevelopmental functions enhancing adult neural homeostasis.14 Animal studies showed that RNA editing is important for cognitive and behavioral responses of the nervous system. Many neurological diseases as well as brain cancer were associated with deregulation of RNA editing.15 Several neurodevelopmental disorders, such as autism spectrum disorders (ASDs), are linked to defects in epigenetic mechanisms. Epigenetic defects such as DNA methylation at certain imprinted gene loci were found associated with neuro- logical disorders like Prader-Willi and Angelman Syndromes.16 There is a considerable amount of evidence about the rela- tion between neurodegenerative diseases and abnormalities in epigenetic mechanisms. The evidence suggested the lack of a simple Mendelian inherited pattern, dysregulation of tran- scriptional mechanisms as well as many pathological RNA alterations. Mechanisms such as microsatellite sequence were found important in regulating cognitive functions, circadian rhythm, and social skills.12 Cancer was found related to some genomes-wide epige- netic changes that enhance tumor induction, progression, invisibility, metastatic ability, and response to the treatment. Cancer epigenetic etiology is a result of multiple inter-related mechanisms such as DNA methylation, non-gene protein- coding, chromatin modifications, and editing of nucleic acids. The abnormalities in these epigenetic mechanisms enhance the silencing of tumor-suppressing genes and the activation of oncogenes. Some CNS cancers such as glioblastomas were found significantly associated with alteration in gene expres- sion profiles that inhibit tumor-suppressing genes.17 In this review, we highlight the genetic causes, clinical manifestations and diagnosis of different CNS malformations. Agenesis of Corpus Callosum (ACC) The corpus callosum (CC) is the largest white matter tract con- necting the two cerebral hemispheres. It comprises 4190 million topographically organized axons. Functionally, it permits the transfer of information between the two cerebral hemispheres, and inhibits any concurrent activity in the contralateral hemi- sphere.18 It contributes to cognition and behavior. Thickness of CC, fiber cross-section and bundle size increases through child- hood and adolescence with slight differences among sexes. Fetal development of CC may be affected by various genetic factors and maternal alcohol abuse. Figure 2 illustrates the normal appearance of the corpus callosum in the mid-sagittal. The CC starts to develop at sixth week of gestation, and continues to dif- ferentiate to attain its shape by the eighteenth to twentieth weeks of gestation; therefore imaging of this structure before 20 weeks may not be optimal (Figure 3).19 In mid-sagittal views of the fetal brain (two-dimensional (2D) ultrasound) the CC appears as a thin anechoic space, lined superiorly and inferiorly by two echogenic lines. Sono- graphic demonstration of the CC requires careful imaging in a center with a high level of expertise to make a full assessment and exclude co-existing brain abnormalities.20 Among infants, 2–3% will have major CC malformations that will be detected at birth or a few weeks after birth. Agen- esis of corpus callosum (ACC) is the most common abnor- mality affecting the CC. It can be partial or complete, isolated or complex (associated with other malformations).21 Other abnormalities of CC are hypoplasia of CC (thinning of CC) and hyperplasia of CC (thickening of CC).20 The most common causes of ACC are gene mutations.22 The overall incidence of ACC is 0.5–70 in 10,000 livebirths.19 Generally, the outcome of isolated ACC is favorable. Patients showed normal intelligence and neuropsychological Fig. 2 Brain magnetic resonance imaging (MRI) T 1 weighted mid-sagittal view showing the normal appearance of corpus callosum (red arrow). Fig. 1 Primary and secondary cerebral vesicles (a) Three primary brain vesicles in 3–4 weeks embryo and (b) Five secondary brain vesicles in 5th-week embryo. Printed with permission.8 3J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System development in up to 70% of cases.23 In the other individuals, deficits in language comprehension, humor, theory of mind and social reasoning are noted. The overall rate of chromosomal abnormality in fetuses with ACC is 18%. Careful imaging in a center with a high level of expertise is required to make a full assessment and to exclude coexisting abnormalities. A wide range of neurological disorders and tumors were associated with epigenetic abnormalities. Defects in chro- matin remodeling have been linked to agenesis of the corpus callosum, mainly chr.22q11.2 microdeletion or duplication. A little data is available about the effect of nuclear signaling and cellular mechanisms in disorders associated with commissural phenotypes such as callosal agenesis. However, a lack of C11orf46 in reference to microdeletion of ch.11p13-14.1 is strongly linked to neurodevelopmental abnormalities which are related to agenesis of the corpus callosum.24 The C11orf46 is a nuclear protein that is expressed in an age-related pattern with a larger amount expressed at pre and post-natal periods in comparison to adulthood. The cellular expression pattern of C11orf46 in the developmental stage of the brain is a nuclear punctate type in NeuroD2-positive cells. The role of C11orf46 in cortical development was demon- strated in animal studies where knockdown of C11orf46 lead to a reduction in corpus callosum thickness. Inhibition of C11orf46 reduced callosal development and commissural connection between cerebral hemispheres.25 The C11orf46 plays an important role in axonal connec- tivity and it is linked to regulators repressive chromatin which is related to trans-callosal connectivity. Moreover, C11orf46 affinity to KMT-RC is a determinant to orderly brain develop- ment. An epigenomic editing trial, working on HEK293 cells, found that C11orf46 could effectively suppress the genes responsible for corpus callosum development.26 Genetic defect: Genetic causes of ACC are heteroge- neous. It could be a part of monogenic syndromes or complex chromosomal abnormalities.19 The overall rate of chromo- somal abnormalities in fetuses with ACC is 18%; nevertheless, recent studies suggest that chromosomal abnormalities are rare in isolated cases.20 The increased use and resolution of comparative genomic hybridization (CGH) have implicated many more genes and genomic loci in corpus callosum devel- opment,27 and have revealed a great diversity of genetic causes for ACC syndromes (Table 1A–1C). At present, however, the Table 1A. Different autosomal dominant gene syndromes and their responsible genes that may be associated with ACC Syndromes Gene Gene Locus Apert Syndrome FGFR2 10q26 Greig Cephalopolysyndaktyly Syndrome GLI3 7p14.1 Miller–Dieker Syndrome Microdeletion 17p13.3 Mowat–Wilson Syndrome ZEB2 2q22 Opitz gbbb Syndrome Microdeletion 22q11.2 Coffin-Siris / Fifth Digit Syndrome ARID1A 1p36.11 ARID1B 6q25.3 SMARCA4 19p13.2 SMARCB1 22q11.23 SMARCE1 17q21.2 SOX11 2p25.2 Rubinstein–Taybi Syndrome Microdeletion 16p13.3 EP300 22q12 Basal cell Nevus Syndrome PTCH 9q22.3 SUFU 10q24.32 Table 1B. Different autosomal recessive gene syndromes and their responsible genes that may be associated with ACC Syndrome Gene Gene Locus Acrocallosal Syndrome KIF7 15q26.1 GLI3 7p13 Andermann Syndrome SLC12A6 15q13-q14 Dincsoy Syndrome Fryns Syndrome PIGN 18q21.33 Fukuyama Congenital Muscular Dystrophy FKTN 9q31.2 Hydrolethalus Syndrome KIF7 15q26.1 Joubert Syndrome 33 autosomal recessive genes Lowry Wood Syndrome RNU4ATAC 2q14.2 Meckel-gruber Syndrome 11 autosomal recessive genes Microcephalic Osteodysplastic Pri- mordial dwarfism type (mopd) і/ііі RNU4ATAC 2q14.2 Muscle Eye Brain Disease Neu-laxova Syndrome PHGDH 1p12 PSAT1 9q21.2 PSPH 7p11.2 Peters-plus Syndrome B3GLCT 13q12.3 Septo-optic Dysplasia Toriello-carey Syndrome Vici Syndrome EPG5 18q12.3-q21.1 Walker-warburg Syndrome POMT1 POMT2 FKTN 9q31.2 Warburg-mikro Syndrome Fig. 3 Prenatal ultrasound of fetal brain midsagittal view showing the normal appearance of corpus callosum at 20 weeks of gestation.20 4 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations in GLI3 gene.37 Debeer et al.38 2003 found a missense mutation in the GLI3 gene resulting in the replacement of arginine amino acid with tryptophan at position 625 of the resultant protein; arg625trp (R625W). This mutation was partially penetrant. Another mutation reported by Kalff-Suske et al.,39 1999 was G-to-T transversion at nucleotide 1627 of the GLI3 gene, resulting in a glu543-to-ter mutation. The GLI3 gene muta- tions may result in another genetic syndrome called Pallis- ter-Hall Syndrome (PHS); but the site and type of mutation totally different from that occurring in GCPS cases. Mutations typically involve exons spanning nucleotides 1813-2103 of the GLI3 cDNA; and most of them were deletions resulting in a frameshift and premature protein termination codon with the final production of truncated proteins.40 Miller–Dieker Syndrome (MDS) It is a rare genetic disorder that comprises severe lissencephaly (smooth brain) and characteristic facial features; including a high and prominent forehead, bitemporal narrowing, short upturned nares, protuberant upper lip with downturned ver- milion border, and small jaw (Figure 5). Manifestations include hypotonia and feeding difficulties. Affected individ- uals suffer from severe mental retardation, seizures, and devel- opmental delay. Other malformations reported in these individuals include omphalocele and congenital heart defects.41 Hypoplasia or complete agenesis of CC is described in most cases of MDS.42 Genetic defect: Approximately 80% of individuals with MDS have a de novo deletion involving the short arm of chro- mosome 17 (17p13.3) in the area involving PAFAH1B1 gene (formerly LIS1); whereas 20% have inherited a deletion from a parent who carries a balanced chromosome rearrangement.43 Most deletions are microdeletions that can be detected in 70% of cases by either high resolution karyotyping or FISH tech- nique (Flourescent in situ hybridization).43 PAFAH1B1 gene Abnormalities may cause MDS, isolated lissencephaly or subcortical band heterotopia (SBH).45 Mowat–Wilson Syndrome (MWS) It is a very rare disorder that its prevalence has been estimated to be 1:50,000 – 1:70,000 live births.46 The MWS is character- ized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, promi- nent chin, and uplifted earlobes with a central depression (Figure 6). The facial features evolve and become more pro- nounced with age.47 Hirschsprung disease (in 44% of cases) or chronic constipation (in 30% of cases) had been described Table 1C. Different X-linked gene syndromes and their respon- sible genes that may be associated with ACC Syndrome Gene Gene Locus Aicardi Syndrome Not known Xp22 Atr-x Syndrome Cranial Frontonasal Syndrome EFNB1 Xq13.1 FG Syndrome CASK Xp11.4 Hydrocephalus Masa Syndrome Lujan-fryns Syndrome MLS Syndrome Oral-facial Digital Syndrome Type 1 proud syndrome Proud Syndrome X-linked Lissencephaly Fig. 4 A = A patient with Apert syndrome, B = Face, C = hoof- shaped hand, D = Syndactyly shape of a rosebud, and E = Syndac- tyly of feet (printed with permission from Rathore et al.,33 2017). cause of 55–70% of cases with ACC cannot be identified by clinical evaluation.28,19 Non-genetic causes of ACC include maternal alcohol use during pregnancy29 or maternal phenylketonuria.30 Apert Syndrome Apert syndrome is characterized by the presence of multi-su- ture craniosynostosis and syndactyly of the hands (fusion of the digits and nails) (Figure 4). Affected individuals have large anteriorly displaced “Anterior Fontanelle” and cloverleaf skull. The ocular abnormalities, hearing loss, and nonprogressive ventriculomegaly had been reported in most cases. Cervical vertebral fusions are found in 68% of affected individuals. Most individuals with Apert syndrome have normal intelli- gence or mild intellectual disability. Abnormalities of the corpus callosum; namely ACC, were described in 23% of cases. Genetic defect: Fibroblast Growth Factor Receptor (FGFR2) gene mutations are linked to many genetic disorders, one of them is Apert syndrome. Heterozygous mutation in FGFR2 mostly reported small intragenic deletions/insertions finally resulting in replacement of serine amino acid with tryptophan amino acid at protein position 252 (written as Ser252Trp). Another mutation replaces proline amino acid with arginine amino acid at position 253 (written as Pro253Arg). These changes are described as “gain-of-func- tion” because they increase the activity of the resultant protein, leading to stronger signaling.31,32 Greig Cephalopolysyndaktyly Syndrome (GCPS) It is a rare genetic disorder characterized by macrocephaly, widely spaced eyes, preaxial polydactyly, and cutaneous syn- dactyly. Affected individuals have developmental delay, intel- lectual disability, and/or seizures. Approximately 200 cases are reported worldwide.34 The ACC is reported in approximately 20% of affected individuals.35 Genetic defect: The GCPS is caused by heterozygous mutation in GLI family zinc finger 3 (GLI3) in 80% of cases, whereas 20% of cases are caused by deletion of the short arm of chromosome 7 (7p14.1) in the area involving GLI3 gene.36 Reported mutations causing GCPS were large deletions, 5J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Fig. 5 Typical facial features of Miller–Dieker syndrome (MDS), including a prominent forehead, bitemporal hollowing, short nose with upturned nares, prominent upper lip, and micrognath- ia. (printed with permission from Kim et al.,44 2011). Fig. 6 Main common features of the Mowat-Wilson Syndrome: large eyebrows, medially flaring and sparse in the middle part, and widely spaced eyes (printed with permission from Garavelli et al.,57 2007). Table 2. Genes and Percentage of CSS caused by a pathogenic variant Gene Gene locus Percentage of CSS caused by pathogenic variants in this gene ARID1A 1p36.11 5% ARID1B 6q25.3, 37% SMARCA2 9p24.3 2% SMARCA4 19p13.2 7% SMARCB1 22q11.23 7% SMARCE1 17q21.2 2% SOX11 2p25.2 2% Unknown 40% with MWS.48 Congenital heart defects; with a predilection for abnormalities of the pulmonary arteries and/or valves, and genitourinary anomalies (particularly hypospadias and cryp- torchidism in males) are frequently described manifestations with MWS.48 Hypoplasia or complete agenesis of CC is described in most cases of MWS.48 Genetic defect: MWS is caused by hetero-zygous muta- tion in ZEB2 gene in 84% of affected individuals.50 15% of MWS patients are caused by deletions in ZEB2 gene.51 1% of cases are caused by chromosome rearrangements at the long arm of chromosome 2; which disrupt ZEB2 gene51 Missense, splice site, or in-frame variants in ZEB2 represent fewer than 2% of cases with typical MWS.49 Yoneda et al.52 2002, reported 3-bp in-frame deletion affecting ZEB2 in an adult with mild intellectual disability, atypical facial features, and megacolon. Zweier et al.53 2006, found a novel splice site variant in the UTR in a patient with facial features and speech delay. Opitz GBBB Syndrome It is a genetic disorder that affects structures along the midline of the body. Patients have characteristic facial features including widely spaced eyes and a cleft lip. Other manifesta- tions include laryngotracheoesophageal abnormalities causing breathing problems and difficulty swallowing. Affected indi- viduals usually suffer from intellectual disability, heart defects, and/or imperforate anus.54 ACC and/or cerebellar vermis and Dandy-Walker malformations were identified in 50% of affected individuals.54 Genetic defect: Opitz GBBB syndrome has two genetic forms one is autosomal dominant (ADOS; type II) and the other is X-linked (OSX; type I) form.55 The autosomal dominant form is caused by microdeletion (submicroscopic) at the long arm of chromosome 22 (22q11.2). Coffin-Siris Syndrome (CSS)/Fifth Digit Syndrome It is a rare genetic disorder characterized by aplasia or hypo- plasia of the distal phalanx/nail of the fifth and additional digits, developmental delay, intellectual disability, distinctive facial features, hypotonia, hypertrichosis, and hearing impair- ment. Congenital anomalies were also reported in individuals affected including malformations of the heart, gastrointestinal, genitourinary, and central nervous systems.56 Genetic defect: CSS is caused by a heterozygous patho- genic variant in one of the genes listed in Table 2. Rubinstein–Taybi Syndrome (RSTS) (Broad Thumb-allux Syndrome) The RSTS is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic facial features include downward slanting of palpebral fissures, high palate, grimacing smile, and talon cusps. Additional fea- tures include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryp- torchidism, feeding problems, recurrent infections, and severe constipation.58 Rarely, RSTS is associated with ACC;59 how- ever, it had been reported in some cases.60 Genetic defect: The RSTS is caused by heterozygous muta- tions in either CREBBP gene (50%-60% of cases)61 or EP300 gene (8%-10% of cases).62 Rusconi et al.63 2015, described 14 patients with RSTS having CREBBP deletions of different sizes; ranging from single exons to whole gene deletions, showing no difference in their phenotype. Somatic mosaicism and mosaic microdeletions have been noted in some individuals with RSTS. They tend to have a mild phenotype.64 6 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. Basal Cell Nevus Syndrome (BCNS)/ Nevoid Basal Cell Carcinoma Syndrome (NBCCS)/ (Gorlin Syndrome) BCNS is a rare autosomal dominant disorder characterized by the development of multiple jaw keratocysts, and/or basal cell carcinomas; manifesting from the third decade onward, skel- etal anomalies, and ectopic calcifications (especially the falx).65,66 Only 5% of children with BCNS develop medullo- blastoma with a peak incidence at one to two years of age.67 More than 100 clinical features that are variable within and among families have been associated with BCNS 68 The preva- lence of BCNS had been reported in some studies to be 1:30,827.69 The ACC in cases with BCNS was estimated in some studies to be 10%.66 Genetic defect: Identification of a heterozygous germline pathogenic variant in either PTCH1 gene or SUFU gene establishes the diagnosis of BCNS. The PTCH1 gene is located on the short arm of chromosome 9 (9q22.3). The PTCH1 gene provides instructions for producing a protein (Patched-1), which functions as a receptor for Sonic Hedgehog protein. Together, Patched-1 and Sonic Hedgehog trigger signals that affect cell development and function that is essential for early development.70 The PTCH1 is seen as a tumor suppressor gene.71 Sim et al.,72 2018, reported frameshift mutations in PTCH1 gene (c.817_818ins(T), c.1226_1227ins(A), and c.2748del(C)), splicing (c.1504-2A>T), and missense (c.385T>C) mutation. Mutations were found in exon 1, 6, 9, 17, and intron 10. The SUFU-related BCNS is associated with a high risk for medulloblastoma of up to 33% compared to that in PTCH1-related BCNS which was less than 2%.65 Acrocallosal Syndrome (ACLS) ACLS is a rare autosomal recessive disorder characterized by pre- or postaxial polydactyly, cutaneous syndactyly, hallux duplication, agenesis of the corpus callosum, widely spaced eyes, macrocephaly, moderate-to-severe ID, intracerebral cysts, seizures, umbilical & inguinal hernias.73 Genetic defect: The ACLS is caused by homozygous mutations (or compound heterozygous) in KIF7 gene. KIF7 is located on the long arm of chromosome 15 (15q26.1) and comprise 19 exons. KIF7 is a 1343 amino acid protein with a kinesin motor, coiled coil, and Gli-binding domains. The ACLS may also result from a heterozygous mutation in GLI3 (7p14.1); the causative gene for Greig cephalopolysyndactyly syndrome (GCPS). The clinical manifestations of ACLS and GCPS overlap significantly; that’s why ACLS is considered the severe form of GCPS.73 The proteins produced from the KIF7 and GLI3 gene are part of the Sonic Hedgehog (SHH) signa- ling pathway (Figure 7). This pathway is involved in cell growth, cell specialization, and the regulation of microtubular dynamics necessary for the proper function of the primary Fig. 7 Schematic overview of Sonic Hedgehog signaling pathway (Cervello et al.,80 2017). 7J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System cilia, and hence genetic disorders involving genes regulating this pathway are called ciliopathies. The resultant proteins in SHH signaling pathway are responsible for patterning of the brain and limbs.74 The KIF7 gene mutations had been linked also to Joubert syndrome, a rare genetic disorder characterized by cerebellar hypoplasia, ataxia, psychomotor delay, and an altered respiratory pattern in the neonatal period. Retinal degeneration, renal cysts, liver fibrosis, and skeletal involve- ment were also described with Joubert syndrome.75 Patho- genic variants in KIF7 reported with ACLS include; in-frame deletion mutation (p.218-221del),76 nonsense, missense, and splice site mutations were also described. Ibisler et al,.77 2015 reported a nonsense mutation in exon 11 of the KIF7 gene (c.2335G>T, p.Glu779). Left side: In the absence of HH ligand, PTCH inhibits Smo allowing GLI to form a complex with Kif7 and SuFu, pro- moting GLI phosphorylation by PKA, CK-1, and GSK-3b. Upon phosphorylation, GLI proteins are processed into tran- scriptional repressors (GLI-R) or are targeted to the proteasome. Right side: The HH ligand binding to PTCH and to co-receptors CDON and BOC and relieves repression of Smo, triggering its interaction with Kif7. This facilitates the release of GLI from SuFu/Fu complex, bypassing proteolytic cleavage. Full-length GLI factors lead to the expression of HH target genes. Andermann Syndrome/Agenesis of Corpus Callosum with Peripheral Neuropathy (ACCPN) It is an autosomal recessive disorder characterized by progres- sive sensorimotor neuropathy with areflexia, developmental delay.78 Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves as early as the first year of life. The 86% of affected individuals develop scoliosis.79 The ACC is present in 60% of affected individuals. Genetic defect: The ACCPN is caused by biallelic patho- genic variants in SLC12A6. The SLC12A6 gene provides instructions for making a protein called K-Cl cotransporter (Electroneutral cotransporter); which is critical for the devel- opment and maintenance of nerve tissue. The SLC12A6 gene is located on the long arm of chromosome 15 (15q13-q14). Small intragenic deletions/insertions and missense, nonsense, and splice-site variants in SLC12A6 were reported in cases with ACCPN. Howard et al.81 2002, identified 4 truncating muta- tions in the SLC12A6 gene. Fryns Syndrome It is a rare autosomal recessive genetic disorder characterized by diaphragmatic defects including diaphragmatic hernia, characteristic facial features, short distal phalanges of the fin- gers and toes, pulmonary hypoplasia, microphthalmia, brain malformations including agenesis of the corpus callosum, and cardiovascular anomalies.82 The prognosis in Fryns syndrome is influenced by the malformations present. Survival beyond the neonatal period is rare.83 Genetic defect: The molecular diagnosis of Fryns syn- drome is established when biallelic pathogenic variants (homozygous/compound heterozygous mutations) in PIGN gene are present in a proband with suggestive clinical findings i.e. diaphragmatic hernia.84 The PIGN gene is located on the long arm of chromosome 18 (18q21.33). This gene encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase-1, an enzyme responsible for GPI anchor to cell surface proteins. Maydan et al.85 2011 determined that the PIGN gene contains 31 exons spanning 142.8 kb. Missense, nonsense, and splice-site variants had been associated with PIGN associated Fryns syndrome e.g. c.2620-1G>A.86 Fukuyama Congenital Muscular Dystrophy (FCMD) FCMD is a rare autosomal recessive congenital muscular dys- trophy characterized by early-infantile hypotonia and weak- ness with contractures of the joints. Affected individuals suffer from intellectual disability and speech delays. The condition is seen primarily in children of Japanese ancestry.87 Ophthalmo- logic abnormalities, including visual impairment in 53% and retinal abnormalities in 32% were also reported in patients suf- fering from FCMD.88 Cobblestone lissencephaly and white matter abnormalities can be detected in the MRI images of the brain of individuals with FCMD89 (Figure 8). Cobblestone Fig. 8 Cobblestone lissencephaly in FCMD (Barkovich,90 2005). (A) Axial T 2 -weighted image showing occipital cobblestone with a thick cortex and smooth outer surface (B) Axial T2-weighted image at a higher level showing polymicrogyria of the frontal lobes. (C) Coronal T 1 -weighted image showing the characteristic cortical cysts in the cerebellar hemispheres (smaller arrows). https://www.omim.org/geneMap/18/207?start=-3&limit=10&highlight=207 8 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. cerebral cortex malformations are associated with congenital muscular dystrophies as in FCMD, Walker–Warburg syn- drome, and muscle–eye–disease of Santavuori.90 The elevated serum creatinine and interstitial fibrosis without muscle degeneration and regeneration seen on histo- pathological examination of muscle biopsies are consistent features of FCMD.91 Genetic defect: The molecular diagnosis of FCMD is con- firmed when biallelic pathogenic variants in FKTN gene are detected in a proband with clinical findings suggestive of FCMD. The FKTN gene is located on the long arm of chromo- some 9 (9q31.2). This gene encodes for a 461-amino acid fukutin protein, which is expressed in various tissues in normal individuals. It is believed that fukutin play an impor- tant role in neuronal migration and glycosylation of Alpha-dys- troglycan (DAG1) of skeletal and cardiac muscle fibers.92,93 Kobayashi et al.87 2017, analyzed FKTN gene in 107 affected individuals that showed the prevalence of the homozy- gous Japanese founder variant (c.*4392_*4393insAB185332.1) among patients; where there is insertion of retrotransposal sequence into 3’-UTR (untranslated region) of FKTN. The second common mutation in FKTN gene associated with FCMD reported in Korea by Lim et al.,94 2010 is (c.647+2084G>T) (p.Arg216SerfsTer10); an intronic mutation that activates a pseudoexon between exons 5 and 6 resulting in a truncated fukutin protein. Saredi et al.95 2009, found 1 bp deletion mutation in FKTN gene in an Italian patient with muscular dystrophy. The muta- tion (c.42del) (p.Thr14_Leu15insTer) results in a premature termination of protein synthesis producing a truncated pro- tein with loss of its function. Joubert Syndrome (JBTS) and Joubert Syndrome and Related Disorders (JSRD) JBTS is characterized by three primary findings: (1) A distinc- tive cerebellar and brain stem malformation called the molar tooth sign (MTS) (Figure 9), (2) Hypotonia and (3) Develop- mental delays. Affected individuals may also suffer from breathing abnormalities (tachypnea or apnea), abnormal eye move- ments, renal disease, ocular colobomas, occipital encepha- locele, hepatic fibrosis or polydactyly.96,97 The ACC is common in 80% of individuals with JBTS.98 Callosal abnormalities are relatively frequent in those with biallelic KIF7 pathogenic variants suggesting overlap with acrocallosal syndrome.99 Genetic defect: The JBTS is diagnosed genetically by the presence of biallelic pathogenic variants in one of the 33 auto- somal recessive JS-related genes or heterozygous mutation in one X-linked gene. Table 3A and 3B show JS related genes and examples of the most common pathologic variants occurring in each gene. 15. Lowry Wood Syndrome (LWS) A rare genetic disorder characterized by epiphyseal dysplasia, short stature, microcephaly and retinal dystrophy.100 Other skeletal manifestations of this disorder included a bilateral absence of radial heads, lateral dislocation of both patellae, and dislocation of both hips.120 Clinical features of microce- phalic osteodysplastic primordial dwarfism type I (MOPD1) Fig. 9 Brain MRI T 1 weighted axial view showing “Molar tooth” sign shown by the arrow in a patient with JBTS (Embiruçu et al., 101 2009) overlap with those of Lowry Wood Syndrome; which is also caused by a biallelic mutation in the RNU4ATAC gene. Genetic defect: The LWS is caused by biallelic pathologic variants in the RNU4ATAC gene encoding a small nuclear RNA (snRNA); located on the long arm of chromosome 2 (2q14.2).100 Shelihan et al.121 2018, identified compound hete- rozygosity in the RNU4ATAC gene, one was for an r.53C-T transition and the other r.8C-A transversion. Other mutations that had been associated with RNU4ATAC gene in cases of Lowry Wood Syndrome were n.46G>A transition, r.5A-C transversion,100 r.120T-G transversion, and r.114G-C transversion.121 Meckel-Gruber Syndrome (MKS)/ Dysencephalia Splanchnocystica The MKS is a rare autosomal recessive lethal ciliopathy charac- terized by bilateral polycystic kidneys, occipital encephalocele and postaxial polydactyly122 (Figure 10). Other abnormalities that could be found in MKS are cleft lip and palate, congenital heart defects, and pulmonary hypoplasia.123 The worldwide incidence of MKS has been estimated to be 1 in 135,000 live births,124 however, it has a higher incidence in some populations where the consanguineous marriage rate is high, for example, Hutterites,125 Finland,126 Kuwaiti Bedouin tribes,127 and in Saudi Arabia.128 The MKS phenotype overlap with other ciliopathies such as Joubert Syndrome (JBTS), COACH Syndrome (cerebellar vermis hypo/aplasia, oligo- phrenia, congenital ataxia, ocular coloboma, and hepatic fibrosis), Oro-facio-Digital Syndrome (OFD), nephronoph- thisis (NPHP), and Bardet–Biedl Syndrome (BBS); that forms a challenge in the diagnosis of MKS.109,129,130 Genetic defect: The molecular diagnosis of MKS is estab- lished when biallelic pathologic variants are found in one of the MKS causing genes. To date, there are 11 autosomal 9J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Table 3A. Joubert Syndrome related Genes and Pathogenic variants Gene Gene locus Pathogenic variants Phenotypic variant (other than molar tooth sign) Ethnic group References 1-AHI1 6q23.3 Missense and frameshift mutations c.2988del (p.Val997fs) Retinal dystrophy, renal disease Bachmann-Gagescu et al., 2015a99 2-CPLANE1 5p13.2 p.Arg2904Ter Tongue hamartomas +/- cleft lip/ palate +/- polydactyly Dutch, French Canadian Vilboux et al., 2017102 3-CC2D2A 4p15.32 c.100C>T (p.Arg34Ter) Renal disease, hepatic disease French Canadian Doherty et al., 2010103 4-CEP290 12q21.32 c.6012-12T>A Retinal dystrophy, renal disease, hepatic disease Japanese popu- lation Suzuki et al., 2016104 5-CSPP1 8q13.1-q13.2 c.363_364delTA Skeletal dysplasia Hutterite Tuz et al., 2014105 6-INPP5E 9q34.3 Missense and frameshift mutations c.1897_1898del (p.Gln633fs) Retinal dystrophy, hepatic disease Vilboux et al., 2017102 7-KIAA0586 14q23.1 c.392del (p.Arg131fs) Skeletal dysplasia Alby et al., 2015106 8-MKS1 17q22 Retinal dystrophy Slaats et al., 2016107 9-NPHP1 2q13 Renal disease French Canadian Vilboux et al., 2017102 10-RPGRIP1L 16q12.2 Renal disease, hepatic disease Delous et al., 2007108 11-TCTN2 12q24.31 Tongue hamartomas +/- cleft lip/ palate +/- polydactyly Bachmann-Gagescu et al., 2015a99 12-TMEM67 8q22.1 Hepatic disease Brancati et al., 2009109 13-TMEM216 11q12.2 p.Arg73Leu Retinal dystrophy, renal disease, tongue hamartomas +/- cleft lip/ palate +/- polydactyly Ashkenazi Jewish Valente et al., 2010110 14-ARL13B 3q11.1-q11.2 Cantagrel et al., 2008111 15-B9D1 17p11.2 Romani et al., 2014112 16-B9D2 19q13.2 Tongue hamartomas +/- cleft lip/ palate +/- polydactyly Bachmann-Gagescu et al., 2015a99 17-C2CD3 11q13.4 Tongue hamartomas +/- cleft lip/ palate +/- polydactyly Bachmann-Gagescu et al., 2015a99 18-CEP41 7q32.2 Retinal dystrophy Lee et al., 2012a113 Table 3B. Joubert Syndrome related Genes and Pathogenic variants Gene Gene locus Pathogenic variants Phenotypic variant (other than molar tooth sign) Ethnic group References 19-CEP104 1p36.32 Srour et al., 2015114 20-CEP120 5q23.2 Tongue hamartomas +/- cleft lip/palate +/- polydactyly 2-Skeletal dysplasia Shaheen et al., 2015b115 21-IFT172 2p23.3 Skeletal dysplasia Halbritter et al., 2013116 22-KATNIP (KIAA0556) 16p12.1 Sanders et al., 2015117 23-KIF7 15q26.1 Tongue hamartomas +/- cleft lip/palate +/- polydactyly, acrocallosal syndrome Dafinger et al., 201175 24-OFD1 Xp22.2 Renal disease, tongue hamartomas +/- cleft lip/palate +/- polydactyly Coene et al., 2009118 25-PDE6D 2q37.1 Thomas et al., 2014119 26-POC1B 12q21.33 27-TCTN1 12q24.11 28-TCTN3 10q24.1 Tongue hamartomas +/- cleft lip/palate +/- polydactyly (Continued) 10 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. recessive genes associated with MKS. Table 4 shows the 11 MKS causative genes with examples of the most common pathologic variant occurring in each gene. The MKS1 gene (609883) is located on the long arm of chromosome 17 (17q22). The MKS1 gene encodes a protein responsible for centriole migration to the apical membrane and the formation of the primary cilium during embryonic life. It is 21,170 bp in length, comprises 18 exons, and encodes a 559-amino acid protein.132 Kyttala et al.133 2006; identified a 29-bp deletion in intron 15 of MKS1 gene (c.1408-35_1408- 7del29) (609883.0001) in 3 Finnish families. The same intronic deletion was found in other Finnish families and families of European descent; it was then denoted as the Finnish founder variant (Campomelic variant).124 Microcephalic Osteodysplastic Primordial Dwarfism Type (MOPD) І/ІІІ The MOPD is a rare autosomal recessive developmental dis- order characterized by extreme intrauterine growth retarda- tion, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations144 (Figure 11). The syn- drome was characterized by Majewski as MOPD types I and III; which were considered parts of the same clinical spectrum Table 3B. Joubert Syndrome related Genes and Pathogenic variants—Continued Gene Gene locus Pathogenic variants Phenotypic variant (other than molar tooth sign) Ethnic group References 29-TMEM107 17p13.1 Retinal dystrophy, tongue hamartomas +/- cleft lip/palate +/- polydactyly 30-TMEM138 11q12.2 Retinal dystrophy, renal disease 31-TMEM231 16q23.1 French Canadian Srour et al., 2015114 32-TMEM237 2q33.1 p.Arg18Ter Renal disease Hutterite 33-TTC21B 2q24.3 34-ZNF423 16q12.1 Renal disease Fig. 10 Showing a fetus aged 16 weeks gestational age (A) Occipital encephalocele and bilateral postaxial polydactyly and (B) Bilateral polycystic kidneys (Hartill et al., 131 2017). and since that time they are combined and denoted as the same disorder.146 The ACC had been reported in patients with MOPD І, whether partial or complete.147,148 Genetic defect: The MOPD І is caused by homozygous or compound heterozygous mutation in the RNU4ATAC gene (601428); the gene that is also associated with Lowry Wood Syndrome. This gene as mentioned above is located on the long arm of chromosome 2 (2q14.2); and is responsible for the production of small nuclear RNA (snRNA) U4atac (a nonpro- tein-coding gene); which is a component of the minor spliceosome.149 The spliceosome is a large ribonucleoprotein (RNP) com- plex that catalyzes the removal of introns from a transcribed pre-mRNA, and the ligation of the flanking exons.150 Splice- osomes are either major or minor that differ in their splicing processes and snRNA components. The minor spliceosome is assembled within the nucleus from 5 subunits; U11, U12, U4atac, and U6atac, together with U5. This type of Splice- osome splices a rare class of pre-mRNA introns, denoted U12- type. Figure 12 shows the detailed structure of the minor spliceosome.151 He et al.149 2011, identified 4 different mutations in the RNU4ATAC gene associated with MOPD І, all these muta- tions ended up in defective U12-dependent splicing (reduced by greater than 90% compared to wildtype U4atac). The muta- tions were genomic 51G-A, genomic 55G-A, genomic 30G-A, 111G-A. Edery et al.152 2011, identified another mutation in RNU4ATAC gene; 51G-A. Abdel-Salam et al.153 2012, identi- fied a homozygous mutation for the genomic 55G-A in RNU- 4ATAC gene (previously reported by He et al. 149 2011), in 2 sibs with mild MOPD1 phenotype. Vici Syndrome Vici Syndrome (OMIM242840) is an autosomal recessive disorder characterized by agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, progressive cardiomyopathy, and combined immunodeficiency154 (Figure 13). Affected individuals suffer also from severe developmental delay, intellectual disability and acquired microcephaly.155 An additional finding is muscle myopathy manifested as progressive hypotonia and elevated serum cre- atinine kinase. Histopathological examination of skeletal muscle fibers by light microscopy reveals wide variation in fiber size, centralized nuclei, and small fibers with high gly- cogen content.156 11J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Table 4. MKS causative genes and the most common pathologic variant Gene Gene Locus Pathogenic variant References MKS1 17q22 Finnish c.1408-35_1408-7del29 Kyttälä et al., 2006133 MKS2 (TMEM216) 11q12.2 Ashkenazi c.218G > T (p.R73L) Edvardson et al., 2010134 MKS3 (TMEM67) 8q22.1 Pakistani c.1575 + 1G > A Smith et al., 2006135 MKS4 (CEP290) 12q21.32 4-BP Del, c.384_387TAGA, (p.Asp128GlufsTer34) Baala et al., 2007b136 MKS5 (RPGRIP1L) 16q12.2 European c.1843A > C (p.T625P) Arts et al., 2007137 MKS6 (CC2D2A) 4p15.32 Finnish c.1762C > T (p.?) Tallila et al., 2008138 MKS7 (NPHP3) 3q22.1 IVS19AS, 2-BP Del, (c.2694-1_2 del) Bergmann et al., 2008139 MKS8 (TCTN2) 12q24.31 IVS13AS, A-G, -2 Shaheen et al., 2011140 MKS9 (B9D1) 17p11.2 505, T-C, +2, (p.Thr82CysfsTer44), splice site donor mutation) Hopp et al., 2011141 MKS10 (B9D2) 19q13.2 301A-C transversion, (p. Ser101Arg) Dowdle et al., 2011142 MKS11 (TMEM231) 16q23.1 c.751G-A transition, (p.Val251SerfsTer9) Shaheen et al., 2013143 Fig 11. A photo of a patient diagnosed with MOPD І at 4 weeks (left) and 6 months of age (right). Note typical facial features with sloping forehead, beaked nose with downturned nasal tip, small low-set ears, sparse hair and joint contractures (both wrists, both elbows, and both knees) (Nagy et al.,145 2012). Patients with Vici Syndrome may develop by time pro- gressive reduction of absolute lymphocyte count and immu- noglobulin level that may necessitate intravenous immunoglobulin (IVIG) therapy.154 Patients usually present with recurrent chest infections, particularly pseudomonas and klebsiella associated with lymphopenia.157 Genetic defect: Vici Syndrome is caused by a biallelic pathogenic variant in EPG5 gene that is located on the long arm of chromosome 18 (18q12.3-q21.1). EPG5 gene encodes a protein that has a role in the autophagy pathway (a conserved lysosomal degradation pathway).158 Cullup et al.158 2013, iden- tified compound heterozygosity (2 different mutations in the same patient) in the EPG5 gene: One was (4588C-T transi- tion), resulting in a (gln1530-to-ter; 615068.0001), and the other one was 1-bp duplication (5704dupT), resulting in a frameshift and premature termination (Tyr1902LeufsTer2; 615068.0002). Ehmke et al.159 2014, identified a homozygous mutation (2 similar mutations in the same patient) in exon 43 of the EPG5 gene; which was (c.7447C-T transition) resulting in an (arg2483-to-ter; 615068.0006). Maillard et al.155 2017, identified compound heterozygosity in the EPG5 gene; One was a (c.4007G-A transition), resulting in a (gly1336-to-glu substitution; 615068.0007), and the other one was 1-bp inser- tion (c.2352_2353insG), resulting in a frameshift and prema- ture termination (Ala785GlyfsTer20; 615068.0008). Primary Microcephaly with or without Cortical Malformation (MCPH) The MCPH is an autosomal recessive neurodevelopmental disorder in which an individual has a head circumference more than 3 standard deviations (SD) below the age- and sex- matched population mean.161 Motor development may be normal or delayed, whereas mental retardation may vary from mild to severely delayed speech acquisition.162,163 At least 17 genetic loci (MCPH1–17) have been impli- cated in MCPH, all of which have now been connected to single genes: MCPH1, WDR62, CDK5RAP2, KNL1, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, and CIT.164 Mutations in WDR62, encoding WD repeat-containing protein 62, are responsible for MCPH2, which is the second most frequent form of MCPH after MCPH5 caused by ASPM mutations. Over 40 pathogenic mutations in WDR62 have already been reported. Cortical malformations may be associated in addi- tion to microcephaly in these patients.165,166 Genetic defect: The MCPH2 is caused by homozygous or compound heterozygous mutation in WDR62 gene (MIM 613583). The WDR62 gene is located on the long arm of chro- mosome 19 (19q13.12). WDR62 gene contains 32 exons and encodes a 1,523-amino acid protein.167 These researchers iden- tified a homozygous mutation in exon 31 of the WDR62 gene in 2 Turkish sibs affected with MCPH2. The mutation was a 4-basepair deletion (TGCC) that resulted in a frameshift and premature termination of the protein (Val1402GlyfsTer12; 613583.0001). Nicholas et al.163 2010, identified a homozygous 1313G-A transition in exon 10 of the WDR62 gene in 2 Paki- stani patients, resulting in an (arg438-to-his substitution; 613583.0006) at a highly conserved residue. Zombor et al.,168 2019, identified a homozygous missense mutation in exon 6 of the WDR62 gene, c.668T>C, p.Phe223Ser. Mutations were detected by whole exome sequencing (WES). 12 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Review B. Alomrani et al. Fig. 13 Brain MRI T 1 weighted mid-sagittal view showing com- plete agenesis of the corpus callosum at the age of 2 months in a patient diagnosed with Vici syndrome (del Campo et al.,160 1999). Fig. 14 L-Serine Biosynthesis Pathway. The first and limiting step of this pathway is the conversion of 3-phosphoglycerate to 3-phos- phohydroxypyruvate by PHGDH (Acuna-Hidalgo et al.,172 2014). Fig. 12 The structure of the minor spliceosome (Chen and Moore, 2015).151 Neu-Laxova Syndrome (NLS) The NLS is a rare autosomal-recessive disorder characterized by characteristic facial features with shortened eyelids, prop- tosis, round gaping mouth, microcephaly, intrauterine growth restriction (IUGR), ichthyosis (skin hyperkeratosis), and flexion deformities169 (Figure 14). The CNS malformations reported with NLS were variable such as abnormal gyration, lissencephaly, agenesis of the corpus callosum, Dandy-Walker anomaly, choroid plexus cysts, or neural-tube defects.170-172 The NLS is caused by mutations in the genes encoding enzymes required for the L-serine biosynthesis pathway; hence it is considered also an inborn error of metabolism (IEM).173 Genetic defect: The molecular diagnosis of NLS is con- firmed by the identification of biallelic pathogenic variants in one of the 3 causative genes; PHGDH gene (phosphoglycerate dehydrogenase gene [MIM 606879]), PSAT1 gene (phosphos- erine aminotransferase 1 gene [MIM 610936]), or PSPH gene (phosphoserine phosphatase gene [MIM 172480]). The PHGDH gene is located on the short arm of chro- mosome 1 (1p12); and encodes 3-phosphoglycerate dehy- drogenase enzyme (the first and rate-limiting enzyme in the L-serine biosynthesis pathway). Shaheen et al.174 2014, iden- tified 2 mutations in the PHGDH gene in Saudi patients clinically diagnosed with NLS. Both mutations were at a region of highly conserved residue within the NAD(P)- binding domain and at the PHGDH dimer interface. The first mutation was c.418G-A transition resulting in a gly140- to-arg substitution; 606879.0007. The second mutation reported by Shaheen et al.174 2014, was c.488G-A transition resulting in a arg163-to-gln substitution; 606879.0008. Both mutations were detected by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing. The PSAT1 gene is located on the long arm of chromo- some 9 (9q21.2); and encodes phosphoserine aminotrans- ferase enzyme, the second enzyme in L-serine biosynthesis pathway. The PSAT gene contains 9 exons and spans 56 kb.175 Acuna-Hidalgo et al.173 (2014) identified a homozygous com- plex insertion/deletion mutation in the last exon of the PSAT1 gene in a fetus with Neu-Laxova Syndrome; (c.1023_1027de- linsAGACCT) resulting in a frameshift and premature termi- nation (Arg342AspfsTer6; 610936.0003). The mutation was detected by detailed reanalysis of exome sequencing. Acu- na-Hidalgo et al.173 (2014), identified another mutation in the highly conserved residue of the PSAT1 gene in 2 stillborn fetuses and a preterm newborn who died within the first week 13J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 1–17 B. Alomrani et al. Review Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System of life, who were all affected by NLS. The mutation was c.296C-T transition resulting in an ala99-to-val substitution; 610936.0004. Conclusion Many malformations of the central nervous system can occur during fetal development. 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