Clinical Presentation and Molecular Characterization of 3 Patients with Vici Syndrome: Two Novel Variants in the EPG5 Gene.

Introduction: Vici syndrome is an ultra-rare, congenital disorder of autophagy characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Patients usually present in the neonatal period or infancy with profound hypotonia, based on information available from the nearly 100 cases reported to date. Case Presentation: We present 3 new cases of Vici syndrome confirmed by genetic analysis of EPG5 gene. The 3 male patients had neonatal hypotonia, progressive microcephaly, psychomotor retardation, recurrent respiratory tract infections, optic atrophy, and failure to thrive, but no cataracts or hepatomegaly. Three disease-causing variants in homozygous state were detected in the EPG5 gene: two novel c.1652C>T and c.7557+2T>C forms; and one previously reported c.7447C>T. The patient, who was homozygous for the c.1652C>T mutation, presented with neonatal onset seizures that had not been reported previously. Discussion/Conclusion: The present study provides data for the evaluation of the natural history and genotype-phenotype correlations for treatment options that are expected to be available in the future.

Imaginative elaboration in agenesis of the corpus callosum: topic modeling and perplexity.

OBJECTIVE: Previous studies have found deficits in imaginative elaboration and social inference to be associated with agenesis of the corpus callosum (ACC; Renteria-Vasquez et al., 2022; Turk et al., 2009). In the current study, Thematic Apperception Test (TAT) responses from a neurotypical control group and a group of individuals with ACC were used to further study the capacity for imaginative elaboration and story coherence. METHOD: Topic modeling was employed utilizing Latent Diritchlet Allocation to characterize the narrative responses to the pictures used in the TAT. A measure of the difference between models (perplexity) was used to compare the topics of the responses of individual participants to the common core model derived from the responses of the control group. Story coherence was tested using sentence-to-sentence Latent Semantic Analysis. RESULTS: Group differences in perplexity were statistically significant overall, and for each card individually (p < .001). There were no differences between the groups in story coherence. CONCLUSIONS: TAT narratives from persons with ACC were normally coherent, but more conventional (i.e., more similar to the core text) compared to those of neurotypical controls. Individuals with ACC can make conventional social inferences about socially ambiguous stimuli, but are restricted in their imaginative elaborations, resulting in less topical variability (lower perplexity values) compared to neurotypical controls.

Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome.

Introduction: Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene. Case Presentation: We report the clinical and genetic characterization of a Syrian patient with a HGPPS2 phenotype and review the previously published cases of HGPPS2. The genetic screening was performed using exome sequencing on Illumina platform. Genetic analysis revealed a novel DCC c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4) variant segregating recessively in the family. This type of variant has not been described previously in the HGPPS2 patients. To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome. Conclusion: The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2. This report expands the knowledge of phenotypic and genotypic spectrum of pathogenic variants causing HGPPS2.

A selective defect in the glial wedge as part of the neuroepithelium disruption in hydrocephalus development in the mouse hyh model is associated with complete corpus callosum dysgenesis.

Introduction: Dysgenesis of the corpus callosum is present in neurodevelopmental disorders and coexists with hydrocephalus in several human congenital syndromes. The mechanisms that underlie the etiology of congenital hydrocephalus and agenesis of the corpus callosum when they coappear during neurodevelopment persist unclear. In this work, the mechanistic relationship between both disorders is investigated in the hyh mouse model for congenital hydrocephalus, which also develops agenesis of the corpus callosum. In this model, hydrocephalus is generated by a defective program in the development of neuroepithelium during its differentiation into radial glial cells. Methods: In this work, the populations implicated in the development of the corpus callosum (callosal neurons, pioneering axons, glial wedge cells, subcallosal sling and indusium griseum glial cells) were studied in wild-type and hyh mutant mice. Immunohistochemistry, mRNA in situ hybridization, axonal tracing experiments, and organotypic cultures from normal and hyh mouse embryos were used. Results: Our results show that the defective program in the neuroepithelium/radial glial cell development in the hyh mutant mouse selectively affects the glial wedge cells. The glial wedge cells are necessary to guide the pioneering axons as they approach the corticoseptal boundary. Our results show that the pioneering callosal axons arising from neurons in the cingulate cortex can extend projections to the interhemispheric midline in normal and hyh mice. However, pioneering axons in the hyh mutant mouse, when approaching the area corresponding to the damaged glial wedge cell population, turned toward the ipsilateral lateral ventricle. This defect occurred before the appearance of ventriculomegaly. Discussion: In conclusion, the abnormal development of the ventricular zone, which appears to be inherent to the etiology of several forms of congenital hydrocephalus, can explain, in some cases, the common association between hydrocephalus and corpus callosum dysgenesis. These results imply that further studies may be needed to understand the corpus callosum dysgenesis etiology when it concurs with hydrocephalus.

Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Threat and adaptation: The maternal lived experience of continuing pregnancy after receiving a prenatal diagnosis of agenesis of the corpus callosum.

One stated objective of prenatal screening and diagnosis is the preparation for delivering a baby with medical needs or disability, however, psychosocial outcomes of parents who received a prenatal diagnosis suggest that this objective is not yet realised. Preparation may be complicated by diagnostic and prognostic uncertainty. A prenatal diagnosis that includes significant uncertainty due to the heterogeneous presentations, classifications, causes and outcomes is agenesis of the corpus callosum. As a neuroanatomical anomaly identified in the second or third trimesters, the diagnosis is likely to cause distress for expectant mothers, yet there is limited guidance for holistic support. To begin to address the paucity of research, this hermeneutic phenomenological study sought to explore, and provide a telling of the maternal experience of continuing pregnancy after a prenatal diagnosis of agenesis of the corpus callosum. Through interviews and a series of online, asynchronous and facilitated focus groups, lived experiences during pregnancy from the time of diagnosis to birth were explored with 26 mothers who participated in this international study. Themes were constructed through reflexive thematic analysis to describe the experience of the lived phenomenon. The first theme, Under Threat, included subthemes of The Threat to the Life of the Baby and Threatened Image of the Expected Family. The second theme, Day to Day Toward Adaptation, included subthemes of Holding it Together and Falling Apart, and More Than Information, Searching for Meaning, Hope and Control. To realise the commonly stated objective of prenatal diagnosis, to support maternal preparation, healthcare professionals require awareness of the profound, yet individual experience of prenatal diagnosis to adequately respond and support mothers through their continued pregnancies. Healthcare services should be designed to flexibly respond in a woman- and family-centred manner to reduce the threat and support maternal adaptation after a prenatal diagnosis.

Diagnóstico prenatal de quistes interhemisféricos asociados a agenesia del cuerpo calloso / Prenatal diagnosis of callosal agenesis with interhemispheric cyst

Introducción: Los quistes interhemisféricos asociados a agenesia del cuerpo calloso constituyen un grupo infrecuente y heterogéneo de anomalías del SNC. Objetivo: Reportar nuestra experiencia en quistes interhemisféricos asociados a agenesia del cuerpo calloso (QIH/ACC), haciendo énfasis en sus características en la neurosonografía (NSG), su comparación con la resonancia magnética (RM) y su evolución clínica posterior. Método: Se incluyeron todas las pacientes con QIH/ACC evaluadas desde el año 2008. En todos los casos se consignaron los datos clínicos, de NSG y de RM cuando se realizó. Se entrevistó telefónicamente a los padres. Resultados: Fueron seleccionados 9 casos con QIH/ACC. De ellos, 5 fueron quistes tipo 1, 3 tuvieron anomalías asociadas y en los 3 hubo una anomalía genética patogénica. Cuatro casos fueron quistes tipo 2, 3 de ellos con un patrón NSG sugerente de síndrome de Aicardi. Hubo una excelente correlación entre NSG y RM, ya fuera esta última realizada ante- o posnatal, particularmente con relación a las malformaciones del desarrollo cortical asociadas al QIH/ACC. Conclusiones: En comparación con la RM y el resultado final, hubo alta concordancia con lo diagnosticado en la NSG, en especial en cuanto a malformaciones del desarrollo cortical asociadas, lo que añade valor al método diagnóstico que ofrecemos a nuestra población consultante.

Background: Callosal agenesis associated with interhemispheric cysts correspond to a rare and heterogenous group of CNS anomalies. Objective: To report our experience in interhemispheric cysts associated with agenesis of the corpus callosum (QIH/ACC), emphasizing its characteristics in neurosonography (NSG), its comparison with magnetic resonance imaging (MRI) and its subsequent clinical evolution. Method: All patients with QIH/ACC evaluated since 2008 were included. In all cases, clinical, NSG and MRI data were recorded when performed. The parents were interviewed by telephone. Results: A total of 9 cases were selected with QIH/ACC. 5 cases were type 1 cysts, 3 of them had associated abnormalities and in all 3 there was a pathogenic genetic anomaly. 4 cases were type 2 cysts, 3 of them with an NSG pattern suggestive of Aicardi syndrome. There was an excellent correlation between NSG and MRI, either before or postnatally, particularly in relation to cortical developmental malformations associated with QIH/ACC. Conclusions: Compared to MRI and the final result, there was high agreement with what was diagnosed in NSG, especially in what corresponds to associated cortical developmental malformations, which adds value to the diagnostic method we offer to our consulting population.

Unravelling the Clinical Co-Morbidity and Risk Factors Associated with Agenesis of the Corpus Callosum.

Agenesis of the Corpus Callosum (ACC) can result in multiple neurological deficits including social and behavioural issues. However, the underlying aetiology, clinical co-morbidity and the contributing risk factors remain elusive, resulting in inaccurate prognosis and delayed therapy. The main objective of this study was to comprehensively describe the epidemiology and clinical co-morbidity associated with patients diagnosed with ACC. The secondary objective was to identify the factors that contribute towards increased risk for ACC. For this, we analysed 22 years (1998-2020) of clinical data across the whole of Wales, UK collected through the Congenital Anomaly Register & Information Service (CARIS) and Public Health Wales (PHW). Our results demonstrate that complete ACC (84.1%) was the prevalent subtype, in comparison to partial ACC. Further, ventriculomegaly/hydrocephalus (26.37%) and ventricular septal defect (21.92%) were identified to be the most prevalent neural malformation (NM) and congenital heart disorder (CHD) in our cohort. Although 12.7% of subjects with ACC had both an NM and CHD, we found no significant association between them (χ2 (1, n = 220) = 3.84, p = 0.33). We found socioeconomic deprivation and increased maternal age contributed towards an increased risk for ACC. To the best of our knowledge, this study for the first time defines the clinical phenotypes and the factors that contribute to ACC within the Welsh population. These findings will be of value to both patients and healthcare professionals, who may take preventative or remedial measures.

Tela-choroidea-to-anterior-cerebral-artery distance (TACAD): novel marker on color Doppler to identify fetuses with complete or partial agenesis of corpus callosum.

OBJECTIVES: To assess objectively the course of the anterior cerebral artery (ACA) by measuring its distance to the tela choroidea in the midsagittal view, and to compare this distance in normal fetuses with that in those with agenesis of the corpus callosum (ACC), a condition known to be associated with an abnormal course of the ACA. METHODS: The tela-choroidea-to-anterior-cerebral-artery distance (TACAD) was measured in the midsagittal view of the brain on color Doppler, between the anterior border of the tela choroidea and the ACA at the level of the callosal genu. Reference ranges in relation to gestational age were established in a prospective, cross-sectional study of 253 normal healthy fetuses between 19 and 36 weeks of gestation. The study group included fetuses with complete ACC (n = 28) or partial ACC (n = 18). RESULTS: TACAD of normal fetuses showed an increase during the second half of pregnancy, with a mean value of 10.1 mm and 14.2 mm at 22 and 30 weeks of gestation, respectively. All (28/28) fetuses with complete ACC and 83% (15/18) of those with partial ACC had significantly shorter TACAD, with mean values of 3.9 mm and 6.6 mm, respectively. CONCLUSIONS: TACAD is a measurement that is simple to obtain during fetal color Doppler neurosonography, which enables quantification of the course of the ACA and pericallosal artery. TACAD is shorter in fetuses with complete or partial ACC than in normal fetuses and provides an objective, quantifiable value, rather than merely descriptive information. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester ventriculomegaly in fetuses with callosal agenesis: Cause or association?

The sonographic findings in four fetuses presenting with ventriculomegaly at first-trimester ultrasound that were subsequently diagnosed as having agenesis of the corpus callosum (ACC) are described. The diagnosis of early ventriculomegaly was suspected subjectively by identification of increased cerebrospinal fluid within the lateral ventricles and confirmed by measuring choroid plexus-to-lateral ventricle length and area ratios. Subsequent scans revealed complete ACC in two cases and partial ACC in the other two. This report adds to the increasing evidence suggesting that first-trimester ventriculomegaly is a strong sonographic marker of underlying brain anomalies, including less evident malformations such as ACC. Detailed second-trimester fetal neurosonography in those women continuing their pregnancies should be performed.

A founder PPIL1 variant underlies a recognizable form of microlissencephaly with pontocerebellar hypoplasia.

Biallelic variants in PPIL1 have been recently found to cause a very rare type of pontocerebellar hypoplasia and congenital microcephaly in which simplified gyral pattern was not observed in all of the patients. Here, we describe a series of nine patients from eight unrelated Egyptian families in whom whole exome sequencing detected a previously reported homozygous missense variant (c.295G>A, p.Ala99Thr) in PPIL1. Haplotype analysis confirmed that this variant has a founder effect in our population. All our patients displayed early onset drug-resistant epilepsy, profound developmental delay, and visual impairment. Remarkably, they presented with recognizable imaging findings showing profound microcephaly, hypoplastic frontal lobe and posteriorly predominant pachygyria, agenesis of corpus callosum with colpocephaly, and pontocerebellar hypoplasia. In addition, Dandy-Walker malformation was evident in three patients. Interestingly, four of our patients exhibited hematopoietic disorder (44% of cases). We compared the phenotype of our patients with other previously reported PPIL1 patients. Our results reinforce the hypothesis that the alterative splicing of PPIL1 causes a heterogeneous phenotype. Further, we affirm that hematopoietic disorder is a common feature of the condition and underscore the role of major spliceosomes in brain development.

Prenatal detection of chromosomal abnormalities and copy number variants in fetuses with corpus callosum agenesis.

OBJECTIVES: The corpus callosum is the main pathway that connects interhemispheric communication. Agenesis of corpus callosum (ACC) have not consistently detected replicate genetic risk factors, potentially due to Etiological heterogeneity of this trait. This study aimed to retrospectively analyze the molecular basis for the ACC and the potential genotyping-phenotyping association and provide the basis for genetic counselling. MATERIAL AND METHODS: Karyotyping and chromosomal microarray analysis were performed for copy number variants. RESULTS: Three cases had 1p36 deletions, two cases had 2q31.2 and 2p16.3 microdeletions, one case had microdeletion of Xq26.3q27.1, five cases involved derived chromosomes due to unbalanced translocations. These cases had variable deletions and duplications with partial overlapping. Phenotypically, besides agenesis of corpus callosum and other brain morphological abnormalities as well as heart abnormalities. CONCLUSIONS: ACC may occur alone or be related to other abnormal clinical phenotypes, and its genetic mechanism is very complicated. These results revealed ACC is associated with a variety of chromosomal abnormalities. The findings of the present study expand the genotypes associated with ACC, and further delineation of the genotype-phenotype correlations for ACC. With current applications of chromosome microarray analysis, congenital submicroscopic copy-number variations in fetuses can be detected more effectively.

Children with corpus callosum anomalies: clinical characteristics and developmental outcomes.

INTRODUCTION: Corpus callosum abnormalities are complex, aetiologically diverse, and clinically heterogeneous conditions. Counselling parents regarding their causes and associated syndromes, and predicting the neurodevelopmental and seizure risk prognosis, is challenging. MATERIAL AND METHODS: We describe the clinical characteristics, associated anomalies, and neurodevelopmental outcomes of children with agenesis of corpus callosum (ACC). Fifty-one neonates with ACC/hypoplasia of the corpus callosum were identified over a 17-year period, and their medical records were retrospectively reviewed. RESULTS: Patients were classified into two groups depending on the presence or absence of associated abnormalities. The first group (17 patients, 33.4%) presented with isolated callosal anomalies. The second group included 34 patients (66.6%) with associated cerebral and extracerebral anomalies. We achieved an identifiable genetic aetiology in 23.5% of our cohort. Magnetic resonance imaging was performed in 28 patients (55%), and of these 39.3% had additional brain anomalies. During the study period, five patients died early in the neonatal period and four were lost to follow up. Of the 42 followed patients, 13 (31%) showed normal neurodevelopment, 13 (31%) showed mild delay, and 16 (38%) had a severe delay. Fifteen (35.7%) had epilepsy. CONCLUSIONS AND CLINICAL IMPLICATIONS: We have confirmed that callosal defects are frequently accompanied by brain and somatic anomalies. Additional abnormalities were shown to be significantly associated with developmental delay and increased risk of epilepsy. We have highlighted essential clinical features that may provide diagnostic clues to physicians and we have given examples of underlying genetic disorders. We have provided recommendations about extended neuroimaging diagnostics and widespread genetic testing that may impact upon daily clinical practice. Paediatric neurologists may therefore use our findings to help base their decisions regarding this matter.

Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature.

PPP2R1A-related neurodevelopmental disorder (NDD) is expressed with autosomal dominant inheritance and is typically caused by a pathogenic de novo PPP2R1A mutation. It is characterized by the predominant features of hypotonia, developmental delay, moderate-to-severe intellectual disability, agenesis of corpus callosum (ACC), ventriculomegaly, and dysmorphic features; however, none of these anomalies have been diagnosed prenatally. We report on the prenatal diagnosis of PPP2R1A-related NDD in two fetuses by whole exome sequencing. Fetus 1 had partial ACC and severe lateral ventriculomegaly; the pathogenic heterozygous c.544C > T (p. Arg182Trp) de novo missense variant in PPP2R1A was detected. Fetus 2 had severe enlargement of the lateral and third ventricles and macrocephaly; they showed a heterozygous likely pathogenic mutation in PPP2R1A gene (c.547C > T, p. Arg183Trp). Both variants were de novo. This was the first study to use trio WES to prenatally analyze fetuses with PPP2R1A variants. Prenatal diagnosis will not only expand the fetal phenotype of this rare genetic condition but also allow for an appropriate counseling of prospective parents regarding pregnancy outcomes.

Imaging Similarities Between Oral-Facial-Digital Syndrome Type 1 and Aicardi Syndrome: Prenatal and Postnatal Magnetic Resonance Imaging (MRI) Findings in 4 Patients.

Prenatal identification by magnetic resonance imaging (MRI) of callosal anomalies, particularly with accompanying intracranial abnormalities, poses a challenge for accurate prognostication and fetal counseling as outcome can vary widely depending on underlying etiology. In female patients, Aicardi syndrome is an important consideration, and prompt postnatal ophthalmologic assessment to identify ocular stigmata of Aicardi syndrome can aid with anticipatory guidance and greater vigilance for seizures. We present a case of a female with fetal and postnatal MRI findings of agenesis of corpus callosum and type 2b interhemispheric cysts, characteristically found in Aicardi syndrome, but was found to have oral-facial-digital syndrome type 1 (OFD1). We also present 3 other companion cases with pre- and postnatal imaging of patients with Aicardi syndrome. These cases highlight the importance of widening the differential diagnosis to also include OFD1 for female patients with callosal anomalies.

Complete agenesis of corpus callosum and unilateral cortical formation anomalies detected on fetal MR imaging: a phenotype strongly associated with the male fetuses.

INTRODUCTION: In a previous study of classifying fetuses with cortical formation abnormalities (CFA) with fetal MR, we noticed a cluster of cases with unilateral CFA and complete agenesis of the corpus callosum (ACC). In this study, we provide a detailed morphological analysis of such fetuses using fetal MR to determine if there are indicators (such as the gender of the fetus) that could be used to delineate a genetic substrate of the phenotype in order to inform future studies. METHODS: We have studied 45 fetuses with the unilateral CFA/ACC phenotype and analysed through an expert consensus panel the location and fine detail of the CFA and the associated findings such as associated anomalies, head size, and sex of the fetus. RESULTS: The frontal lobe was significantly more frequently involved by CFA when compared with other lobes (p < 0.001) but no preference for the left or right hemisphere. CFA most often consisted of excessive/dysmorphic sulcation. The CFA/ACC phenotype was overwhelmingly more frequent in male fetuses (M:F 4.5:1-p < 0.0001). The most frequent associated findings were: ventriculomegaly (16/45 fetuses) and interhemispheric cysts (12/45 cases). CONCLUSIONS: This report highlights the specific phenotype of unilateral CFA/ACC that is much more common in male fetuses. This finding provides a starting point to study possible sex-linked genetic abnormalities that underpin the unilateral CFA/ACC phenotype. KEY POINTS: • We collected fetuses with unilateral cortical formation abnormality and callosal agenesis. • That distinctive neuroimaging phenotype has a strong male gender prevalence (over 80%). • This observation forms the basis of studies about outcomes and genetic substrates.

Vici syndrome in Israel: Clinical and molecular insights.

Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals. Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome. Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder. Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician's diagnostic toolbox and may aid in facilitating identification of affected individuals.

An Adult With Agenesis of Splenium of Corpus Callosum: A Case Report.

A 22-year-old Hispanic immigrant presented to the emergency department after having a witnessed seizure. The patient was born and raised in Columbia and had a history of ventricular septal defect repair at the age of five years. Computer tomography (CT) of brain showed an unusual demonstration -"heterotopia of gray matter"- and the follow-up magnetic resonance imaging (MRI) revealed absence of splenium part of corpus callosum. The patient received a loading dose of IV antiepileptic medications and was then transitioned to oral dose. He was then discharged with seizure prophylaxis and referred for a follow-up at another tertiary care hospital for further workup. This case led to a management dilemma as the role of seizure prophylaxis in genetic brain malformations is not well established.

De Novo GLI3 Pathogenic Variants May Cause Hypotonia and a Range of Brain Malformations Without Skeletal Abnormalities.

BACKGROUND: GLI3 encodes a zinc finger transcription factor that plays a role in the sonic hedgehog pathway. Germline pathogenic GLI3 variants are associated with Greig cephalopolysyndactyly and Pallister-Hall syndromes, two syndromes involving brain malformation and polydactyly. METHODS: We identified patients with pathogenic GLI3 variants and brain malformations in the absence of polydactyly or other skeletal malformation. RESULTS: Two patients were identified. Patient #1 is a 4-year-old boy with hypotonia and global developmental delay. Brain MRI showed a focal cortical dysplasia, but he had no history of seizures. Genetic testing identified a de novo likely pathogenic GLI3 variant: c.4453A>T, p.Asn1485Tyr. Patient #2 is a 4-year-old boy with hypotonia, macrocephaly, and global developmental delay. His brain MRI showed partial agenesis of the corpus callosum, dilatation of the right lateral ventricle, and absent hippocampal commissure. Genetic testing identified a de novo pathogenic GLI3 variant: c.4236_4237del, p.Gln1414AspfsTer21. Neither patient had polydactyly or any apparent skeletal abnormality. CONCLUSIONS: These patients widen the spectrum of clinical features that may be associated with GLI3 pathogenic variants to include hypotonia, focal cortical dysplasia, and other brain malformations, in the absence of apparent skeletal malformation. Further study is needed to determine if GLI3 pathogenic variants are a more common cause of focal cortical dysplasia or corpus callosum agenesis than presently recognized.