Cerebellar Vermis Hypoplasia Research Articles

Turner syndrome associated with cerebellar abnormalities

We present an autopsied fetus with Turner syndrome (TS), obtained after a therapeutic abortion at the Clinic of Obstetrics and Gynecology at the University Hospital, Plovdiv, Bulgaria. It was a female fetus weighing 75 g. The chorionic villus sampling followed by karyotyping established monosomy XO. The fetal autopsy confirmed agenesis of the cerebellar vermis and cerebellar hypoplasia. The immunohistochemical study of the brain with S100 protein (S100), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and cluster of differentiation 68 was taken into consideration. The presence of extensive gliosis reaction is proved in the cerebellar structures of TS by the positivity of glial markers: (GFAP) and S100 protein. The quantity of neurons proved by NSE marker is probably associated with the deficiency of differentiation and cell migration caused by inhibition in the development of young cells. The presented case of TS found a new phenotype with cerebellar abnormalities described for the first time.

ZFP423 regulates early patterning and multiciliogenesis in the hindbrain choroid plexus.

The choroid plexus (ChP) is a secretory tissue that produces cerebrospinal fluid (CSF) secreted into the ventricular system. It is a monolayer of secretory, multiciliated epithelial cells derived from neuroepithelial progenitors and overlying a stroma of mesenchymal cells of mesodermal origin. Zfp423, which encodes a Kruppel-type zinc-finger transcription factor essential for cerebellar development and mutated in rare cases of cerebellar vermis hypoplasia/Joubert syndrome and other ciliopathies, is expressed in the hindbrain roof plate, from which the IV ventricle ChP arises, and, later, in mesenchymal cells, which give rise to the stroma and leptomeninges. Mouse Zfp423 mutants display a marked reduction of the hindbrain ChP (hChP), which: (1) fails to express established markers of its secretory function and genes implicated in its development and maintenance (Lmx1a and Otx2); (2) shows a perturbed expression of signaling pathways previously unexplored in hChP patterning (Wnt3); and (3) displays a lack of multiciliated epithelial cells and a profound dysregulation of master genes of multiciliogenesis (Gmnc). Our results propose that Zfp423 is a master gene and one of the earliest known determinants of hChP development.

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly.

Peters anomaly (PA) is a congenital corneal opacity associated with corneo-lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N-cadherin, a transmembrane protein that mediates cell-cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association.

Newborn with multiple congenital anomalies in newborn, intensive care unit suggestive of joubert syndrome and related disorder with an atypical presentation

Joubert syndrome (JS) is a rare autosomal recessive disorder with key finding of cerebellar vermis hypoplasia with a complex brainstem malformation that comprises the molar tooth sign on axial magnetic resonance images. This syndrome is difficult to diagnose clinically because of its variable phenotype. Molar tooth sign is not specific for JS. Another entity is termed as Joubert syndrome and related disorders (JSRD). Although the molar tooth sign and other important clinical features of the JS may be seen in these syndromes, they usually have supplementary prominent features. Author present a case of Joubert syndrome and related disorder in a term newborn delivered in the hospital of Government Medical College, Haldwani with multiple congenital anomalies. Macrocephaly, facial dysmorphism, polydactyly left hand and bilateral ballotable lumbar lump (multicystic dysplastic kidney). MRI showed molar tooth configuration of superior cerebellar peduncles, dilatation of lateral and third ventricles with aqueductal stenosis with arachnoid cyst (unusual association).

Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome.

BackgroundJoubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid‐hindbrain malformation called the “molar tooth sign” on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS.MethodsWhole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT‐PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690).ResultsWe identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode.ConclusionOur study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.

Biometry of the Cerebellar Vermis and Brain Stem in Children: MR Imaging Reference Data from Measurements in 718 Children.

Objective and quantitative data to define cerebellar vermis and/or brain stem hypoplasia in children are lacking. Our aim was to provide MR imaging biometric references for the cerebellar vermis and brain stem from a large cohort of children with normal cerebellums. The MR imaging data were retrospectively selected from our hospital data base from January 1, 2014, to December 31, 2017. All MR imaging examinations of children between 1 day and 15 years of age, including midline sagittal sections, were included. Children with a clinical history or MR imaging abnormalities that may affect the posterior fossa were excluded. We manually measured four 2D parameters: vermian height, anterior-posterior diameter of the vermis, anterior-posterior diameter of the midbrain-pons junction, and anterior-posterior midpons diameter. The inter- and intraobserver agreement was evaluated. Seven hundred eighteen children were included (372 boys and 346 girls), from 1 day to 15 years of age. Normal values (third to 97th percentiles) were provided for each parameter. The vermis parameters showed a rapid growth phase during the first year, a slower growth until the fifth year, and finally a near-plateau phase. The brain stem parameters showed more progressive growth. The intra- and interobserver agreement was excellent for all parameters. We provide reference biometric data of the vermis and the brain stem using simple and reproducible measurements that are easy to use in daily practice. The relevance of these 2D measurements should be further validated in diseases associated with cerebellar abnormalities.

Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.

Brain abnormalities in infantile esotropia as predictor for consecutive exotropia

ABSTRACT Cerebral palsy, neurological abnormalities, prematurity or periventricular lesions may affect motor and sensory fusion mechanisms that favorably control eye alignment. White matter damage of immaturity (WMDI) is a form of white matter brain injury characterized by the necrosis of white matter near the lateral ventricles. In these cases, it is difficult to establish fusion after strabismus surgery and consecutive deviations may be seen more frequently especially in association with WMDI. The aim of this study is to evaluate and compare the cerebral magnetic resonance imaging (MRI) findings in operated infantile esotropia cases with and without consecutive exotropia and to relate them to the occurance of consecutive exotropia. Seventeen patients that had consecutive exotropia after bilateral medial rectus recession surgery for infantile esotropia were included in this study (group 1) and patients that were operated with the same diagnosis with a successful surgical outcome (≤10 PD of deviation) were recruited as group 2. Age, sex, consanguinity, associated systemic and neurological diseases, prematurity, visual acuity, angle of deviations at first visit, at last and follow-up visit and after surgery, cycloplegic retinoscopy, fundus and cerebral MRI findings were recorded. Demographic and clinical findings of patients in two groups and MRI findings were evaluated and compared. The mean age at the time of first examination was 8.21 ± 6.62 and 7.45 ± 4.94 months in infantile esotropia patients with (group 1) and without consecutive exotropia (group 2), respectively. The mean cycloplegic refractive errors (+1.92 ± 1.57 D vs. +2.30 ± 1.10 D), the mean preoperative angle of deviation (46.33 ± 18.8 PD vs. 34.8 ± 12.5 PD), sex, percentage of consanguinity, percentage of prematurity, presence of latent nystagmus, dissociated vertical deviation and amblyopia and fundus findings were similar in both groups. Patients with consecutive exotropia had a mean deviation angle of 37.5 ± 9.48 PD postoperatively. Cerebral MRI findings were consistent with WMDI (three patients), myelinization delay (one patient), septooptic dysplasia (one patient) and periventricular cysts (one patient) in group 1. Cerebellar hemispheres and vermis hypoplasia (one patient), myelinization delay (one patient), cerebellar atrophy (one patient) were the MRI findings of patients in group 2. White matter damage of immaturity was only present in the consecutive exotropia group. This finding may suggest that WMDI can be a risk factor for consecutive deviation in infantile esotropia patients.

Severe neurodevelopmental disease caused by a homozygous TLK2 variant

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

Teaching Video NeuroImages: Characteristic head jerks in congenital oculomotor apraxia due to Joubert syndrome

A 29-year-old man presented in our clinic due to repetitive head jerks since his first year of life, which were previously diagnosed as tics. Examination revealed difficulties initiating voluntary saccades in the horizontal plane and disturbed hand–eye coordination with compensatory head thrusts (video and figure, A). The diagnosis of congenital oculomotor apraxia was made. Brain MRI revealed cerebellar vermis hypoplasia with elongated superior peduncles (“molar tooth sign”; figure, B) characteristic for Joubert syndrome, a rare autosomal-recessive ciliopathy with genetic heterogeneity.1 Joubert syndrome is a common etiology of congenital oculomotor apraxia, a condition first described by Cogan,2 who considered compensatory head jerks diagnostic.

Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

Objective JBTS17 is a major gene mutated in ciliopathies such as Joubert syndrome and oral-facial-digital syndrome type VI. Most patients with loss of function mutations in JBTS17 exhibit cerebellar vermis hypoplasia and brainstem malformation. However, some patients with JBTS17 mutations show microcephaly and abnormal gyration. We examined potential roles of JBTS17 in neurogenesis to understand the pathological mechanism of JBTS17-related cortical abnormalities. Methods We examined subcellular localization and cell-cycle-dependent expression of JBTS17 proteins using anti-JBTS17 antibodies and JBTS17 expression vectors. We also performed knockdown experiments to determined roles of JBTS17 in human cells, and demonstrated mitotic functions of JBTS17 using immunostaining and live imaging. We examined the involvement of JBTS17 in cortical neurogenesis using a mouse in utero electroporation technique. Results We found that JBTS17 localizes to the kinetochore and the level of JBTS17 is regulated by cell-cycle-dependent proteolysis. Depletion of JBTS17 disrupts chromosome alignment and spindle pole orientation, resulting in mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex interferes with the mitotic progression of neural progenitors and the migration of postmitotic neurons. Interpretation LIS1 is implicated in lissencephaly, but altered dosage of LIS1 has been also associated with microcephaly syndromes. Our results suggest that JBTS17 contributes to mitotic progression by interacting with LIS1, and abnormal mitosis is an underlying mechanism of the microcephaly phenotype in JBTS17-related ciliopathies. We propose that understanding extraciliary roles of ciliopathy proteins is important to elucidate pathological mechanisms underlying diverse ciliopathy phenotypes. ANN NEUROL 2019.

The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity.

Joubert syndrome (JS; MIM PS213300) is a rare, typically autosomal recessive disorder characterized by cerebellar vermis hypoplasia and a distinctive malformation of the cerebellum and brainstem identified as the “molar tooth sign” on brain MRI. Other universal features include hypotonia with later ataxia and intellectual disability/developmental delay, with additional features consisting of oculomotor apraxia and abnormal respiratory pattern. Notably, other, more variable features include renal cystic disease, typically nephronophthisis, retinal dystrophy, and congenital hepatic fibrosis; skeletal changes such as polydactyly and findings consistent with short-rib skeletal dysplasias are also seen in many subjects. These pleiotropic features are typical of a number of disorders of the primary cilium, and make the identification of causal genes challenging given the significant overlap between JS and other ciliopathy conditions such as nephronophthisis and Meckel, Bardet-Biedl, and COACH syndromes. This review will describe the features of JS, characterize the 35 known genes associated with the condition, and describe some of the genetic conundrums of JS, such as the heterogeneity of founder effects, lack of genotype-phenotype correlations, and role of genetic modifiers. Finally, aspects of JS and related ciliopathies that may pave the way for development of therapeutic interventions, including gene therapy, will be described.

Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis.

JBTS17 is a major gene mutated in ciliopathies such as Joubert syndrome and oral-facial-digital syndrome type VI. Most patients with loss of function mutations in JBTS17 exhibit cerebellar vermis hypoplasia and brainstem malformation. However, some patients with JBTS17 mutations show microcephaly and abnormal gyration. We examined potential roles of JBTS17 in neurogenesis to understand the pathological mechanism of JBTS17-related cortical abnormalities. We examined subcellular localization and cell-cycle-dependent expression of JBTS17 proteins using anti-JBTS17 antibodies and JBTS17 expression vectors. We also performed knockdown experiments to determined roles of JBTS17 in human cells, and demonstrated mitotic functions of JBTS17 using immunostaining and live imaging. We examined the involvement of JBTS17 in cortical neurogenesis using a mouse in utero electroporation technique. We found that JBTS17 localizes to the kinetochore and the level of JBTS17 is regulated by cell-cycle-dependent proteolysis. Depletion of JBTS17 disrupts chromosome alignment and spindle pole orientation, resulting in mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex interferes with the mitotic progression of neural progenitors and the migration of postmitotic neurons. LIS1 is implicated in lissencephaly, but altered dosage of LIS1 has been also associated with microcephaly syndromes. Our results suggest that JBTS17 contributes to mitotic progression by interacting with LIS1, and abnormal mitosis is an underlying mechanism of the microcephaly phenotype in JBTS17-related ciliopathies. We propose that understanding extraciliary roles of ciliopathy proteins is important to elucidate pathological mechanisms underlying diverse ciliopathy phenotypes. ANN NEUROL 2019.

Neuroimaging Findings in Moebius Sequence.

Moebius sequence comprises a spectrum of brain congenital malformations predominantly affecting the function of multiple cranial nerves. Reported neuroimaging findings are heterogeneous and based on case reports or small case series. Our goal was to describe the neuroimaging findings of Moebius sequence in a large population of patients scanned with MR imaging. An observational cross-sectional study was performed to assess brain MR imaging findings in 38 patients with Moebius syndrome studied between 2013 and 2016. Retrospective analysis of MR imaging studies showed flattening of the floor of the fourth ventricle floor secondary to a bilateral absent facial colliculus in 38 patients (100%) and unilateral absence in 1. A hypoplastic pons was found in 23 patients (60.5%). Mesencephalic malformations consisted of tectal beaking in 15 patients (39.5%) and increased anteroposterior midbrain diameter with a shallow interpeduncular cistern in 12 (31.6%). Infratentorial arachnoid cysts were found in 5 patients (13.2%), and cerebellar vermis hypoplasia, in 2 (5.3%). Supratentorial findings included the following: thalamic fusion (26.3%), periventricular nodular heterotopias (26.3%), ventriculomegaly (26.3%), callosal abnormalities (23.7%), and hippocampal malrotations (23.7%). Findings seen in this large patient cohort agreed with previously published reports. Flattening of the fourth ventricle floor secondary to a bilaterally absent facial colliculus was the most frequent MR imaging finding. The presence of other brain stem and cerebellar malformations as well as supratentorial abnormalities may help explain clinical symptoms and achieve a correct diagnosis.

Joubert Sendromlu Hastanın Skolyoz Cerrahisinde Anestezi Yönetimi: Olgu Sunumu

Joubert Syndrome is a rare, autosomal recessive AR disorder characterized byneurologic findings as hypotonia, ataxia, physhcomotor developmental delay, abnormal respiratory pattern and abnormal eye movements. Molar tooth sign caused by cerebellar vermis hypoplasia is a neuroradiologic diagnostic criteria in cranial magnetic resonance imaging MRI . Scolisosis is common in these patients due to hypotonia during the early developmental period. In this article we presented our anesthesia management during scoliosis correction surgery in a patient with Joubert Syndrome

RHOMBOENCEPHALOSYNAPSIS MR-SEMIOTICS AND DIFFERENTIAL DIAGNOSIS

Rombencephalosynapsys (RES) is a rare variant of anomalies of the posterior cranial fossa structures characterized by dysplastic fusion of cerebellar hemispheres and absence or hypoplasia of cerebellar vermis. Purpose: to demonstrate the possibilities of modern neuroimaging in the RES diagnosis and to identify the main markers of the differential diagnosis in posterior fossa structures (PFS) anomalies. In the department of Radiology of Russian Children’s Clinical Hospital, we observed 3 patients with RES (1 girl and 2 boys). Patients age varied from 3 months to 9 years. The studies were performed on high-field MR system GE Discovery 750 W 3 T. Results: оn MRI in patients with RES we identified the spectrum of dysplastic anomalies of the vermis, from complete absence to partial aplasia with preservation of its anterior part. Also, there were 2 case with cerebellar dysplastic features, resemling RES. The transcerebellar sulci were estimated as the a clue diagnostic marker of RES. Conclusion: High-field MRI is the preferred diagnostic tool in the definition and differentiation of the developmental anomalies of the PFC in the children, especially in patients with RES.

Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia.

Sox2 is a transcription factor active in the nervous system, within different cell types, ranging from radial glia neural stem cells to a few specific types of differentiated glia and neurons. Mutations in the human SOX2 transcription factor gene cause various central nervous system (CNS) abnormalities, involving hippocampus and eye defects, as well as ataxia. Conditional Sox2 mutation in mouse, with different Cre transgenes, previously recapitulated different essential features of the disease, such as hippocampus and eye defects. In the cerebellum, Sox2 is active from early embryogenesis in the neural progenitors of the cerebellar primordium; Sox2 expression is maintained, postnatally, within Bergmann glia (BG), a differentiated cell type essential for Purkinje neurons functionality and correct motor control. By performing Sox2 Cre-mediated ablation in the developing and postnatal mouse cerebellum, we reproduced ataxia features. Embryonic Sox2 deletion (with Wnt1Cre) leads to reduction of the cerebellar vermis, known to be commonly related to ataxia, preceded by deregulation of Otx2 and Gbx2, critical regulators of vermis development. Postnatally, BG is progressively disorganized, mislocalized, and reduced in mutants. Sox2 postnatal deletion, specifically induced in glia (with GLAST-CreERT2), reproduces the BG defect, and causes (milder) ataxic features. Our results define a role for Sox2 in cerebellar function and development, and identify a functional requirement for Sox2 within postnatal BG, of potential relevance for ataxia in mouse mutants, and in human patients.

Antenatal Detection of Mosaic Trisomy 22 with a Finding of Blake’s Pouch Cyst

AbstractThe authors report a case of mosaic trisomy 22 diagnosed antenatally by amniocentesis at 19 weeks. The ultrasound finding was an isolated posterior fossa fluid collection in the brain with features possibly suggestive of a Blake’s Pouch cyst with doubtful hypoplasia of cerebellar vermis. The karyotype of the amniocytes was mos47, + 22[6]/46[8] with two separate clones of cells. Trisomy 22 was seen in one clone (43%) while the other clone (57%) had a normal karyotype. On postnatal examination after termination, there were no dysmorphic features. A selective autopsy of the fetal brain was suggestive of normal posterior fossa anatomy with normal cerebellar vermis which retrospectively confirmed the diagnosis of a Blake’s pouch cyst.

Caudal Fossa Ratio in Normal Dogs and Eurasier Dogs with VLDLR-Associated Genetic Cerebellar Hypoplasia.

Cerebellar and hindbrain malformations, such as cerebellar hypoplasia (CH), vermis hypoplasia, and Dandy–Walker malformation, occur in dogs as well as in humans. Neuroimaging is essential for a precise description of these malformations and defining translational animal models. Neuroimaging is increasingly performed in puppies, but there is a lack of data on developmental changes in the caudal fossa, which can impair assessment of caudal fossa size in this age group. The purpose of this study was to validate caudal fossa ratio (CFR) in dogs and to explore CFR in Eurasier dogs with genetic CH. CFR was calculated from midsagittal brain images of 130 dogs as caudal fossa area/total cranial cavity area. In addition, the volume of the caudal fossa was measured in 64 randomly selected dogs from this group. Repeated measurements were used to investigate inter- and intra-rater variability and influence of imaging modality. Furthermore, the influence of age, weight, and breed was explored. The CFR was a reliable parameter with negligible influence from the examiners, imaging modality, and weight of the dog. The midsagittal area of the caudal fossa and the volume of the caudal fossa correlated closely with each other. In this study, we observed a smaller CFR in puppies. The CFR in adult dogs lies within 0.255 and 0.330, while CFR is smaller in puppies up to 4 months of age. Besides age, there was also an effect of breed, which should be explored in larger data sets. Measurements of CFR in Eurasier dogs with genetic CH caused by a mutation in the very-low-density-lipoprotein-receptor gene revealed the presence of two variants, one with an enlarged caudal fossa and one with a normal to small caudal fossa. This observation indicates that there is phenotypic heterogeneity and interaction between the developing cerebellum and the surrounding mesenchyme in this animal model.

Prenatal diagnosis of posterior fossa anomalies: Additional value of chromosomal microarray analysis in fetuses with cerebellar hypoplasia.

To elucidate the relationship between copy number variations (CNVs) detected by high-resolution chromosomal microarray analysis (CMA) and the type of prenatal posterior fossa anomalies (PFAs), especially cerebellar hypoplasia (CH). This study involved 77 pregnancies with PFAs who underwent CMA. Chromosomal aberrations including pathogenic CNVs and variants of unknown significance were detected in 31.2% (24/77) of all cases by CMA and in 18.5% (12/65) in fetuses with normal karyotypes. The high detection rate of clinically significant CNVs was evident in fetuses with cerebellar hypoplasia (54.6%, 6/11), vermis hypoplasia (33.3%, 1/3), and Dandy-Walker malformation (25.0%, 3/12). Compare with fetuses without other anomalies, cases with CH and additional malformations had the higher CMA detection rate (33.3% vs 88.9%). Three cases of isolated unilateral CH with intact vermis and normal CMA result had normal outcomes. The deletion of 5p15, 6q terminal deletion, and X chromosome aberrations were the most frequent genetic defects associated with cerebellar hypoplasia. Among fetuses with PFA, those with cerebellar hypoplasia, vermis hypoplasia, or Dandy-Walker malformation are at the highest risk of clinically significant CNVs. Chromosomal microarray analysis revealed the most frequent chromosomal aberrations associated with CH.