Truncating variants of the sterol recognition region of SHH cause hypertelorism phenotype rather than hypotelorism-holoprosencephaly.

Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia-mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss-of-function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13-year-old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25-year-old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism-holoprosencephaly phenotype associated with loss-of-function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.

A novel 3q interstitial deletion including GATA2 and ZNF148: A case report.

GATA2 and ZNF148 have both been mapped to chromosome 3q. Pathogenic variants in GATA2 have been associated with immunodeficiency and high risk for myelodysplasia, acute myeloid leukemia, and chronic myelomonocytic leukemia. Gain-of-function variants in ZNF148 have previously been suggested as a mechanism for agenesis of the corpus callosum (ACC). Here, we report a novel 10.4 Mb interstitial deletion on 3q12.33q22.1 including GATA2 and ZNF148 in a child with developmental delay, agenesis of the corpus callosum, and vertebral segmentation defects. With this diagnosis, we were able to suggest preemptive referrals to hematology/oncology and allergy/immunology for close monitoring of early myelodysplasia. We also propose a possible link between ZNF148 loss of function variants and ACC.

Fetal agenesis of corpus callosum: chromosomal copy number abnormalities and postnatal follow-up.

OBJECTIVE: Agenesis of the corpus callosum (ACC) is an anomaly that can occur in fetuses during pregnancy. However, there is currently no treatment for fetal ACC. Therefore, we conducted a retrospective analysis of obstetric outcomes of fetal ACC to explore the relationship between fetal ACC phenotypes and chromosomal copy number abnormalities. METHODS AND RESULTS: Amniotic fluid or umbilical cord blood were extracted from pregnant women with fetal ACC for karyotype analysis and chromosomal microarray analysis (CMA). Among the 48 fetuses with ACC, 22 (45.8%, 22/48) had isolated ACC, and 26 (54.2%, 26/48) had non-isolated ACC. Chromosomal abnormalities were detected via karyotype analysis in four cases. In addition to the four cases of pathogenic copy number variations (CNVs) detected using karyotype analysis, CMA revealed two cases of pathogenic CNVs with 17q12 microduplication and 16p12.2 microdeletion. The obstetric outcomes of 26 patients with non-isolated ACC were followed up, and 17 chose to terminate the pregnancy. In addition, seven of the nine cases with non-isolated ACC showed no obvious abnormality during postnatal follow-up, whereas only one case with normal CMA showed an abnormal phenotype at six months. Of the 22 patients with isolated ACC, six chose to terminate the pregnancy. Postnatal follow-up of 16 isolated ACC cases revealed only one with benign CNV, presenting with intellectual disability. CONCLUSION: Pregnant women with fetal ACC should be offered prenatal CMA, particularly non-isolated ACC. Patients with ACC should undergo prolonged postnatal follow-up, and appropriate intervention should be provided if necessary.

Prenatal Diagnosed Agenesis of the Corpus Callosum: Identifying the Underlying Genetic Etiologies.

OBJECTIVE: To assess the genetic etiologies underlying agenesis of the corpus callosum (ACC) and its pregnancy outcomes in the era of next-generation sequencing. METHODS: A retrospective analysis was conducted on prospectively collected prenatal ACC cases in which amniocentesis was performed between January 2016 and December 2022. ACC was divided into non-isolated and isolated according to the presence or absence of ultrasound abnormalities. Chromosomal microarray analysis (CMA), karyotyping and exome sequencing (ES) were performed after genetic counseling. Pregnancy outcomes were assessed by pediatric neurosurgeons and were followed up by telephone through their parents. RESULTS: Sixty-eight fetuses with ACC were enrolled in this study. CMA detected eight cases with pathogenic copy number variants (CNVs) and all were non-isolated ACC, with a detection rate of 11.8% (8/68). Among the CMA abnormalities, the majority (6/8) were detectable by karyotyping. ES was performed in 26 cases with normal CMA, revealing pathogenic or likely pathogenic gene variations in 12 cases (46.2%, 12/26), involving L1CMA, SMARCB1, PPP2R1A, ARID1B, USP34, CDC42, NFIA and DCC genes. The detection rates of ES in isolated and non-isolated ACC were 40% (6/15) and 54.5% (6/11), respectively. After excluding cases where pregnancy was terminated (56 cases), there were 12 live births, ranging in age from 15 months to 7 years. Of these, 91.7% (11 out of 12) demonstrated normal neurodevelopmental outcomes. Specifically, all five cases with isolated ACC and negative ES results exhibited normal neurodevelopment. The remaining six cases with favorable outcomes were all isolated ACC, among which ES identified variants of DCC and USP34 gene in one each case. The other four cases were CMA-negative and declined ES. CONCLUSIONS: We highlight the efficacy of prenatal ES in determining the genetic etiology of ACC, whether isolated or not. Favorable neurodevelopmental outcomes were observed when ACC was isolated and with normal ES results.

Genetic etiology of agenesis of the corpus callosum: a retrospective single-center cohort analysis of 114 fetuses.

PURPOSE: The identification and prognosis of the agenesis of the corpus callosum (ACC) for prenatal consultation are complex and currently unclear. This study aims to explore the correlated genetic mutations of prenatal ACC. METHODS: We retrospectively analyzed 114 prenatal cases of ACC. All cases (n = 114) were subjected to chromosomal microarray analysis (CMA), and 66 CMA-negative cases underwent prenatal exome sequencing (pES) for further analysis. RESULTS: CMA was diagnosed positively in 15/114 (13.2%) cases and pES was diagnosed positively in 24/66 (36.4%) CMA-negative cases. The detection rate of genetic causes between complete and partial ACCs was not significantly different (P > 0.05). Between isolated and non-isolated (other anomalies present) ACCs, the diagnostic rate of pES in non-isolated cases was significantly higher (P < 0.001), while CMA results did not differ (P > 0.05). The diagnostic rate of CMA was significantly increased in cases combined with intracranial and extracranial malformations (P = 0.014), while no CMA positivity was detected in cases combined with only intracranial malformations. CONCLUSION: For fetuses with prenatal ACC, further pES analysis should be recommended after negative CMA results. Chromosome abnormalities are less likely to occur when ACC with only intracranial malformations combined.

Anomalies of the Corpus Callosum in Prenatal Ultrasound: A Narrative Review for Diagnosis and Further Counseling.

The corpus callosum is the major interhemispheric tract that plays an important role in neurological function. Understanding the etiology and embryology development helps the ultrasound diagnosis for disorders of the corpus callosum and further counseling. The nonvisualization of cavum septum pellucidum or dysmorphic cavum septum pellucidum in axial view are indirect signs for beginners to diagnose complete agenesis of corpus callosum (cACC) and partial agenesis of the corpus callosum (pACC). Further coronal view, sagittal view, and fetal magnetic resonance imaging are also important for evaluation. Genetic testing plays an essential tool in anomalies of corpus callosum by revealing the underlying genetic pathophysiology, such as chromosomal anomalies and numerous monogenetic disorders in 30%-45% of ACC. Diagnosis and prediction of prognosis for hypoplasia or hyperplasia of the corpus callosum are more difficult compared to cACC and pACC because of the limited reports in the literature. However, the complex types often had poorer prognostic outcomes compared to the isolated types. Hence, it is important to evaluate and follow fetal conditions thoroughly to rule out intracranial or extracranial anomalies in other systems.

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Imaging characteristics and neurosurgical outcome in subjects with agenesis of the corpus callosum and interhemispheric cysts.

PURPOSE: To explore the relationships between clinical-radiological features and surgical outcomes in subjects with interhemispheric cysts (IHC) and corpus callosum anomalies. METHODS: We reviewed the clinico-radiological and neurosurgical data of 38 patients surgically treated with endoscopic fenestration, shunting, or combined approaches from 2000 to 2018 (24 males, median age 9 years). Pre- and postoperative changes in IHC volume were calculated. Outcome assessment was based on clinico-radiological data. Group comparisons were performed using χ2, Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests. RESULTS: Median age at first surgery was 4 months (mean follow-up 8.3 years). Eighteen individuals (47.3%) required > 1 intervention due to IHC regrowth and/or shunt malfunction. Larger preoperative IHC volume (P = .008) and younger age at surgery (P = .016) were associated with cyst regrowth. At last follow-up, mean cystic volume was 307.8 cm3, with IHC volume reduction > 66% in 19/38 (50%) subjects. The neurological outcome was good in 14/38 subjects (36.8%), fair in 18/38 (47.3%), and poor in 6/38 (15.7%). There were no differences in the postoperative cyst volume with respect to either the type of first surgery or overall surgery type. Higher absolute postoperative IHC reduction was observed in subjects who underwent both IHC fenestration and shunting procedures (P < .0001). No differences in neurological outcome were found according to patient age at surgery or degree of IHC reduction. CONCLUSION: Endoscopic fenestration and shunting approaches are both effective but often require multiple procedures especially in younger patients. Larger IHC are more frequently complicated by cyst regrowth after surgery.

Social anxiety disorder in an adolescent with agenesis of the corpus callosum: a case report.

BACKGROUND: The agenesis of corpus callosum (ACC) could impair the connectivity of the hemispheres of the cerebral cortex and cause cognitive impairments, social and behavioral issues, and even psychiatric disorders. Although social deficits are common in ACC patients, it is rare for a social anxiety disorder to occur. CASE PRESENTATION: To report a 17-year-old adolescent with complete ACC associated with social anxiety disorder, depression, impulsive behavior, and other neurodevelopmental defects such as intellectual disabilities. His avoidance and fear were improved after treatment with sertraline. CONCLUSIONS: This is the first report of social anxiety disorder in ACC patients. The possible relationship between brain structural abnormities and anxiety syndrome should be investigated in more studies.

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation.

PURPOSE: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC). METHODS: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered. RESULTS: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy. CONCLUSION: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.

An analysis of 109 fetuses with prenatal diagnosis of complete agenesis of corpus callosum.

BACKGROUND: Agenesis of the corpus callosum (ACC) is the most frequent commissural malformation of the brain. It continues to be an important cause of the pregnancy termination associated with the central nervous system (CNS). OBJECTIVE: The aim of the study is to provide a comprehensive assessment of fetuses with diagnosis of complete ACC, as well as postnatal neurodevelopmental outcomes. METHODS: The data of 75,843 fetuses were screened for evaluation of complete ACC between 2003 and 2017, and a total of 109 cases with complete ACC were included in the study. ACC was considered isolated when no additional anomalies were detected, and ACC was considered complex when additional anomalies were present. RESULTS: The prevalence of complete ACC was 9.4 per 10,000 live births, and the incidence was ranged from 1.8 to 16.6 per 10,000 person-years. Patients with isolated ACC had a significantly higher survival when compared with patients with complex ACC (97.4%, n = 38/39 vs. 68.8%, n = 22/32, P = 0.001).The most important cause of death were congenital heart disease and/or respiratory failure during neonatal period. Developmental and intellectual disabilities were significantly higher in the complex ACC cases (P < 0.001). Postnatal neurodevelopmental outcomes were completely normal in 79.4% of cases with isolated ACC. CONCLUSIONS: Isolated complete ACC is usually associated with a favorable outcome. The most important prognostic factors are the presence or absence of associated congenital anomalies.

Ultrasound and Magnetic Resonance Imaging of Agenesis of the Corpus Callosum in Fetuses: Frontal Horns and Cavum Septi Pellucidi Are Clues to Earlier Diagnosis.

OBJECTIVES: We hypothesized that: (1) fetal frontal horn (FH) morphology and their proximity to the cavum septi pellucidi (CSP) can assist in suspecting complete agenesis of the corpus callosum (cACC) and partial agenesis of the corpus callosum (pACC) earlier than known indirect ultrasound (US) findings; (2) FHs assist in differentiating a true CSP from a pseudocavum; and (3) magnetic resonance imaging (MRI) is useful in learning FH morphology and pseudocavum etiology. METHODS: Thirty-two patients with cACC and 9 with pACC were identified on an Institutional Review Board-approved retrospective review. Of the 41 cases, 40 had prenatal US, and 21 had prenatal MRI; 17 had follow-up neonatal US, and 14 had follow-up neonatal MRI. Variables evaluated retrospectively were the presence of a CSP or a pseudocavum, ventricle size and shape, and FH shape (comma, trident, parallel, golf club, enlarged, or fused). Displacement between the inferior edge of the FH and the midline or cavum/pseudocavum was measured. RESULTS: Fetal FHs had an abnormal shape in 77% ≤20 weeks' gestation, 86% ≤24 weeks, and 90% >24 weeks. Frontal horns were laterally displaced greater than 2 mm in 85% ≤20 weeks, 91% ≤24 weeks, and 95% >24 weeks. The CSP was absent in 100% of cACC cases and 78% of pACC cases, and a pseudocavum was present in 88% of cACC cases and 78% of pACC cases across gestation. Magnetic resonance imaging confirmed US pseudocavums to be focal interhemispheric fluid or an elevated/dilated third ventricle. CONCLUSIONS: Frontal horns assist in assessing ACC ≤24 weeks and throughout gestation. Pseudocavums, often simulating CSPs, are common in ACC. Frontal horn lateral displacement and abnormal morphology, recognized by MRI correlations, are helpful in differentiating a pseudocavum from a true CSP. A normal CSP should not be cleared on screening US unless normally shaped FHs are seen directly adjacent to it.

Natural History of Ventriculomegaly in Fetal Agenesis of the Corpus Callosum.

OBJECTIVES: To assess the natural evolution of the size of the fetal lateral ventricles throughout pregnancy in fetuses with callosal anomalies. METHODS: Cases of fetal callosal anomalies were retrospectively classified as isolated or complex based on the presence of other structural or genetic anomalies. Longitudinal ultrasound studies were reviewed, and postnatal outcomes were retrieved for isolated cases. RESULTS: In 135 fetuses, those who first presented after 24 weeks' gestation were more likely to have ventriculomegaly (n = 58 of 68 [85%]) than those who presented before 24 weeks (n = 39 of 67 [58%]; P < .001). In 79 cases that had longitudinal follow-up, the mean increase in ventricular width was 0.6 mm/wk, without a significant difference between isolated and complex cases (mean ± SD, 0.6 ± 1.5 versus 0.6 ± 1.1 mm; P = .45). CONCLUSIONS: Callosal anomalies are associated with progressive ventriculomegaly on prenatal ultrasound imaging, without a difference between isolated and complex anomalies. This feature should be considered part of the disease spectrum. The consequence of progressive ventriculomegaly on the long-term neurodevelopmental outcome is still unknown, and further studies should be aimed at obtaining long-term follow-up of these cases.

The Neuropsychological Syndrome of Agenesis of the Corpus Callosum.

BACKGROUND: Agenesis of the corpus callosum (AgCC) involves congenital absence of all or part of the corpus callosum. Because the disorder can only be firmly diagnosed via neuroradiology, it has a short research history, and only recently has the cognitive syndrome become clear. PURPOSE: Our purpose is to review the primary deficits in AgCC that constitute the core syndrome. CONCLUSIONS: The cores syndrome includes: (1) reduced interhemispheric transfer of sensory-motor information; (2) reduced cognitive processing speed; and (3) deficits in complex reasoning and novel problem-solving. These domains do not appear to reflect different neuroanatomical abnormalities, but rather different domains of expression of reduced interhemispheric communication from callosal absence. IMPLICATIONS: These core deficits are expressed across various domains of cognitive, behavioral, and social functioning. The impact of these deficits varies across development and may be moderated by individual factors such as co-occurrence of other neurodevelopmental conditions, general intellectual capacity, and environmental support. (JINS, 2019, 25, 324-330).

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Low-level expression of EPG5 leads to an attenuated Vici syndrome phenotype.

Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8-year-old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well-controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099-6C > G). Reverse transcription-polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17-which maintains an open reading frame-in 77% of the transcript, along with 23% expression of wild-type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild-type mRNA may result in a significantly attenuated Vici syndrome phenotype.

Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

A Neuropsychological Profile for Agenesis of the Corpus Callosum? Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children.

OBJECTIVES: Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. METHODS: Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. RESULTS: In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. CONCLUSIONS: This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention. (JINS, 2018, 24, 445-455).

Anatomical subgroup analysis of the MERIDIAN cohort: failed commissuration.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with either agenesis or hypogenesis of the corpus callosum (referred to collectively as failed commissuration) on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with failed commissuration (with or without ventriculomegaly) diagnosed on ultrasound in women who had MRI assessment within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was studied, as well as indicators of diagnostic confidence and effects on prognosis/clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: In the MERIDIAN cohort, 79 fetuses were diagnosed with failed commissuration on ultrasound (55 with agenesis and 24 with hypogenesis of the corpus callosum). The diagnostic accuracy for detecting failed commissuration was 34.2% for ultrasound and 94.9% for MRI (difference, 60.7% (95% CI, 47.6-73.9%), P < 0.0001). The diagnostic accuracy for detecting hypogenesis of the corpus callosum as a discrete entity was 8.3% for ultrasound and 87.5% for MRI, and for detecting agenesis of the corpus callosum as a distinct entity was 40.0% for ultrasound and 92.7% for MRI. There was a statistically significant improvement in 'appropriate' diagnostic confidence when using MRI as assessed by the score-based weighted average method (P < 0.0001). Prognostic information given to the women changed in 36/79 (45.6%) cases after MRI and its overall effect on clinical management was 'significant', 'major' or 'decisive' in 35/79 cases (44.3%). CONCLUSIONS: Our data suggest that any woman whose fetus has failed commissuration as the only intracranial finding detected on ultrasound should have MRI examination for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.