Pontine Hypoplasia Research Articles

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

Dissecting CASK: Novel splice site variant associated with male MICPCH phenotype.

CASK (MIM#300172), encoding a calcium/calmodulin-dependent serine protein kinase, is crucial for synaptic transmission and gene regulation during neural development. Pathogenic variants of CASK are known to cause several neurodevelopmental disorders, including X-linked intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH). This study introduces a novel, de novo synonymous CASK variant (NM_001367721.1: c.1737G>A, p.(Glu579=)), discovered in a male patient diagnosed with MICPCH, characterized by microcephaly, developmental delay, visual impairment, and myoclonic seizures. The variant disrupts a donor splice-site at the end of exon 18. Transcriptomic analysis of blood identified 12 different CASK transcripts secondary to the synonymous variant. Nearly one third of these transcripts were predicted to result in nonsense mediated decay or protein degradation. Protein modeling revealed structural alterations in the PDZ functional domain of CASK, due to exon 18 deletion. Our findings highlight the utility of transcriptomic analysis in demonstrating the underlying disease mechanism in neurodevelopmental disorders.

Novel Genetic Variant in HUWE1: Prenatal and Postnatal Neuroimaging Phenotype.

To provide a comprehensive description of neuroradiologic findings in a patient with a probable pathogenic variant of HUWE1, particularly in relation to pontine and cerebellar hypoplasia. We first report prenatal and postnatal neuroradiologic phenotype of a female patient carrying a HUWE1 likely pathogenic variant and discuss its function. An ultrasound shows borderline ventriculomegaly, rotated cerebellar vermis, and dysgenetic corpus callosum. An MR study identify a short, thin corpus callosum, falcine sinus persistence, reduced cerebellar vermis size, wide inferior IV ventricle, and reduced pontine bulging. HUWE1 is a gene encoding an E3 ubitiquine ligase protein involved in nervous system development, function, and disease. The mechanisms by which HUWE1 gene affects nervous system are still largely unclear, but a growing body of literature described disease-causing variants in this gene. This report may help prenatal diagnostic experts in consider also this entity, especially when dealing with pontine and cerebellar hypoplasia findings.

Multiplex Consanguineous Family Highlights CLASP1 as a Candidate Gene for Lissencephaly.

Noncentrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CLASP family of molecules. To date, no human monogenic disorder has been associated with the CLASP1 gene. In this study, we aimed to delineate the clinical and neuroradiologic phenotype associated with biallelic CLASP1 variants. We analyzed clinical characteristics, MRI data, and genotypes of a cohort of 3 patients with homozygous variants in CLASP1. Homozygous CLASP1 variant is associated with primary microcephaly, severe neurodevelopmental delay, and early-onset refractory epilepsy. The neuroradiologic phenotype comprises a highly recognizable combination of classic lissencephaly, with the posterior gradient more severe than the anterior gradient, a thin/hypoplastic splenium of the corpus callosum, mild enlargement of the lateral ventricles primarily posteriorly with a squared pattern, and pontine hypoplasia. This study underscores the role of CLASP1 in brain development and suggests that the identified variant disrupts CLASP1 interaction with the microtubule cytoskeleton, contributing to lissencephaly pathogenesis.

MED23 pathogenic variant: genomic-phenotypic analysis.

The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain's neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI.

363 A CRISPR/dCas9 Epigenetic Therapuetic Approach for CASK-Related MICPCH

OBJECTIVES/GOALS: CASK-related microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a rare X-linked neurodevelopmental disorder caused by mutations in calcium/calmodulin-dependent serine protein kinase (CASK). We aim to rescue CASK expression via an CRISPR/dCas9 epigenetic therapeutic and create iPSC-based CASK relevant in vitro model systems. METHODS/STUDY POPULATION: As females have two X-chromosomes, disease causing mutations present with a 50/50 expression of mutant and wildtype, due to the mosaicism caused by random X-chromosome inactivation (XCI). This project will adapt an established CRISPR/dCas9 epigenetic approach to rescue expression from the silenced, wild-type CASK allele. We aim to accomplish this through testing different dCas9 orthologues and a guide RNA screen targeting the CASK promoter. Constructs will be tested for optimal targeting efficacy in vitro and assessed via RT-qPCR. Additionally, epigenetic modifications from our approach will be analyzed through bisulfite sequencing. We also aim to apply this epigenetic rescue technology in disease relevant cell lines and eventually in engineered patient mutation iPSC-derived neurons. RESULTS/ANTICIPATED RESULTS: Our results show the ability to target CASK and assess gene expression changes with CRISPR/dCas9 paired with an epigenetic modifier and transcriptional activator. Additionally, our fibroblast model with nonpathogenic single nucleotide polymorphisms within CASKallow for allele specific analysis of our targeted reactivation. We anticipate that following an increase of CASK expression, there would be a decrease in region specific promoter methylation. Further, with the identification of clinically described disease-causing point mutations that result in a loss of function of CASK protein, induction of the mutant sequence onto a healthy cell background will result in a similar reduction of CASK protein in our cell model. DISCUSSION/SIGNIFICANCE: This project will demonstrate the first therapeutic avenue for CASK-related MICPCH, and the potential to utilize targeted X-reactivation as a platform approach for X-linked disorders. Further, investigation of smaller dCas9 orthologues prepares our approach for future translational applications such as packaging into AAV for delivery.

Diverse Clinical Phenotypes of CASK-Related Disorders and Multiple Functional Domains of CASK Protein.

CASK-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, congenital nystagmus, and neurodevelopmental disorders. Whole-genome sequencing has identified various mutations, including nonsense and missense mutations, from patients with CASK-related disorders, revealing correlations between specific mutations and clinical phenotypes. Notably, missense mutations associated with epilepsy and intellectual disability were found throughout the whole region of the CASK protein, while missense mutations related to microcephaly and MICPCH were restricted in certain domains. To investigate the pathophysiology of CASK-related disorders, research groups have employed diverse methods, including the generation of CASK knockout mice and the supplementation of CASK to rescue the phenotypes. These approaches have yielded valuable insights into the identification of functional domains of the CASK protein associated with a specific phenotype. Additionally, recent advancements in the AI-based prediction of protein structure, such as AlphaFold2, and the application of genome-editing techniques to generate CASK mutant mice carrying missense mutations from patients with CASK-related disorders, allow us to understand the pathophysiology of CASK-related disorders in more depth and to develop novel therapeutic methods for the fundamental treatment of CASK-related disorders.

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome.

Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome.

Expanding the natural history of CASK-related disorders to the prenatal period.

To assess whether microcephaly with pontine and cerebellar hypoplasia (MICPCH) could manifest in the prenatal period in patients with calcium/calmodulin-dependent serine protein kinase (CASK) gene disorders. In this international multicentre retrospective study, we contacted a CASK parents' social media group and colleagues with expertise in cerebellar malformations and asked them to supply clinical and imaging information. Centiles and standard deviations (SD) were calculated according to age by nomograms. The study consisted of 49 patients (44 females and 5 males). Information regarding prenatal head circumference was available in 19 patients; 11 out of 19 had a fetal head circumference below -2SD (range -4.1SD to -2.02SD, mean gestational age at diagnosis 20 weeks). Progressive prenatal deceleration of head circumference growth rate was observed in 15 out of 19. At birth, 20 out of 42 had a head circumference below -2SD. A total of 6 out of 15fetuses had a TCD z-score below -2 (range -5.88 to -2.02). This study expands the natural history of CASK-related disorders to the prenatal period, showing evidence of progressive deceleration of head circumference growth rate, head circumference below -2SD, or small TCD. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements and genetic studies are advised in the presence of progressive deceleration of head circumference growth rates or small TCD. Progressive deceleration of fetal head circumference growth rate can be observed. A small transcerebellar diameter is an additional important manifestation. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements are advised when measurements are within the low range of norm.

Two heterozygous mutations in the calcium/calmodulin-dependent serine protein kinase gene (CASK) in cases with developmental disorders.

The calcium/calmodulin-dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK-linked disorders. From clinical and genetic mutational analyses, relevant data in 2 Han Chinese patients were collected and analyzed. Real-time quantitative PCR (RT-qPCR) was performed to investigate the CASK expression levels in the patients. The X-chromosome inactivation (XCI) patterns of the patients and their nuclear families were tested by quantitation of methylation of the polymorphic human androgen receptor (HUMARA) locus. Two Han Chinese patients both presented with intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH). Two de novo mutations of c.82C>T (p.Arg28*) and c.846C>G (p.Tyr282*) in CASK have been investigated and predicted to be deleterious, which have produced truncated proteins. The functional protein association network of STRING (http://string-db.org) generated three-dimensional (3D) atomic models based on protein sequences in CASK and two Arg28 and Tyr282 residues were marked. RT-qPCR showed lower copy numbers of CASK expression in the patients than in their parents, as well as the sex- and age- matched control groups. Patient 1 showed a skewed XCI pattern, while no related changes noted in patient 2. Patients carrying different nonsense variants may have different degrees of different clinical phenotypes. This study expands the spectrum of genotype and phenotype correlations of CASK-linked disorders in the Han Chinese ethnicity and provides new insights into the molecular mechanism.

CASK loss of function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons

SummaryLoss-of-function (LOF) mutations in CASK cause severe developmental phenotypes, including microcephaly with pontine and cerebellar hypoplasia, X-linked intellectual disability, and autism. Unraveling the pathological mechanisms of CASK-related disorders has been challenging owing to limited human cellular models to study the dynamic roles of this molecule during neuronal maturation and synapse development. Here, we investigate cell-autonomous functions of CASK in cortical excitatory induced neurons (iNs) generated from CASK knockout (KO) isogenic human embryonic stem cells (hESCs) using gene expression, morphometrics, and electrophysiology. While immature CASK KO iNs show robust neuronal outgrowth, mature CASK KO iNs display severe defects in synaptic transmission and synchronized network activity without compromising neuronal morphology and synapse numbers. In the developing human cortical excitatory neurons, CASK functions to promote both structural integrity and establishment of cortical excitatory neuronal networks. These results lay the foundation for future studies identifying suppressors of such phenotypes relevant to human patients.

A novel, likely pathogenic variant in UBTF-related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype.

A de novo, pathogenic, missense variant in UBTF, c.628G>A p.Glu210Lys, has been described as the cause of an emerging neurodegenerative disorder, Childhood-Onset Neurodegeneration with Brain Atrophy (CONDBA). The p.Glu210Lys alteration yields a positively charged stretch of three lysine residues. Functional studies confirmed this change results in a stronger interaction with negatively charged DNA and gain-of-function activity when compared to the wild-type sequence. The CONDBA phenotype reported in association with p.Glu210Lys consists of normal early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood. The current proband presented at 9 months of age with baseline developmental delay and more extensive neuroradiological findings, including pontine hypoplasia, thalamic volume loss and signal abnormality, and hypomyelination. Like the recurrent CONDBA p.Glu210Lys variant, this novel variant, c.608A>G p.(Gln203Arg) lies within the highly conserved second HMG-box homology domain and involves the replacement of the wild-type residue with a positively charged residue, arginine. Computational structural modeling demonstrates that this amino acid substitution potentiates the interaction between UBTF and DNA, likely resulting in a gain-of-function effect for the UBTF protein, UBF. Here we present a new divergent phenotype associated with a novel, likely pathogenic, missense variant at a different position in the UBTF gene, c.608A>G p.(Gln203Arg).

Pathogenic variants in CASK: Expanding the genotype-phenotype correlations.

Pathogenic variants in CASK, an X-linked gene that plays a role in brain development and synaptic function, are the cause of both microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XLID) with or without nystagmus. MICPCH is caused by loss of function variants in CASK, typically affects females, and is associated with moderate-to-severe intellectual disability (ID). Additional findings, present in about one-third of individuals, include feeding difficulties, ophthalmologic issues, hypertonicity, epilepsy, and sensorineural hearing loss. Only a few affected males with MICPCH phenotype have been reported and most have had profound developmental disability and intractable epilepsy. The XLID phenotype is typically caused by missense variants and most often manifests in males; carrier females are mildly affected or unaffected. Nystagmus is often present. In total, over 175 patients have been reported in the literature. We now report an additional 11 patients with pathogenic variants in CASK that expand these phenotypes and reported genotype-phenotype correlations.

A novel missense variant in the CASK gene causes intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia

BackgroundVariants in the CASK gene result in a wide range of observed phenotypes in humans, such as FG Syndrome 4 and intellectual disabilities. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder that affects females and is characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Variants in CASK are the main genetic cause of MICPCH. Variants in CASK can explain most patients with MICPCH, but there are still some patients whose disease aetiology cannot be explained.Case presentationAn 11-month-old female diagnosed with MICPCH exhibited general developmental delays, microcephaly, and cerebellar hypoplasia. Whole-exome sequencing (WES) was used to find a novel heterozygous missense variant (NM_003688.3: c.638T>G) of CASK in this patient. Strikingly, this variant reduced the expression of CASK at the protein level but not at the mRNA level. By using protein structure prediction analysis, this study found that the amino acid change caused by the variant resulted in further changes in the stability of the protein structure, and these changes caused the downregulation of protein expression and loss of protein function.ConclusionIn this study, we first reported a novel heterozygous pathogenic variant and a causative mechanism of MICPCH. The amino acid change cause by this variant led to changes in the protein structure and a decrease in its stability, which caused a loss of protein function. This study could be helpful to the genetic diagnosis of this disease.

A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: a case report and literature review

BackgroundThe pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by variant. We reported a Chinese male newborn with a de novo variant in CASK gene.Case presentationWe present an 18-day-old baby with growth retardation and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense variant c.764G > A of CASK gene. The variant changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.ConclusionsIn this paper, a de novo variant of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported. CASK variants cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Clinical and genetic analysis of a child with mental retardation and microcephaly with pontine and cerebellar hypoplasia

To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member. The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant. The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

PurposePathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. MethodsThrough international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. ResultsWe identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1−/− knockouts. ConclusionOur work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.

L1CAM variants cause two distinct imaging phenotypes on fetal MRI.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic–mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.

Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant

Pathogenic variants of the ADGRG1 gene are associated with bilateral frontoparietal polymicrogyria, defined radiologically by polymicrogyria with an anterior-posterior gradient, pontine and cerebellar hypoplasia and patchy white matter abnormalities. We report a novel homozygous ADGRG1 variant with atypical features. The patient presented at 8 months of age with motor delay, esotropia, hypotonia with hyporeflexia and subsequently developed refractory epilepsy. At the last assessment, aged 12 years, head control, sitting and language were not acquired. Magnetic resonance imaging revealed diffuse polymicrogyria with relative sparing of the anterior temporal lobes, without an anterior-posterior gradient, diffuse hypomyelination and pontine and cerebellar hypoplasia. A panel targeting brain morphogenesis defects yielded an unreported homozygous ADGRG1 nonsense variant (dbSNP rs746634404), present in the heterozygous state in both parents. We report a novel ADGRG1 variant associated with diffuse polymicrogyria without an identifiable anterior-posterior gradient, diffuse hypomyelination and a severe motor and cognitive phenotype. Our case highlights the phenotypic diversity of ADGRG1 pathogenic variants and the clinico-anatomical overlap between recognized polymicrogyria syndromes.