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Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin., Competing Interests: Declaration of interests D.R. is a cofounder of Constellation and Fulcrum Pharmaceuticals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes., (© 2021 Wiley Periodicals LLC.)

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause., (© 2020 Wiley Periodicals LLC.)

Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin α2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI., (© 2020 American Association of Neuropathologists, Inc.)

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that caused a public health emergency in the Americas when an outbreak in Brazil became linked to congenital microcephaly. Understanding how ZIKV could evade the innate immune defenses of the mother, placenta, and fetus has become central to determining how the virus can traffic into the fetal brain. ZIKV, like other flaviviruses, evades host innate immune responses by leveraging viral proteins and other processes that occur during viral replication to allow spread to the placenta. Within the placenta, there are diverse cell types with coreceptors for ZIKV entry, creating an opportunity for the virus to establish a reservoir for replication and infect the fetus. The fetal brain is vulnerable to ZIKV, particularly during the first trimester, when it is beginning a dynamic process, to form highly complex and specialized regions orchestrated by neuroprogenitor cells. In this review, we provide a conceptual framework to understand the different routes for viral trafficking into the fetal brain and the eye, which are most likely to occur early and later in pregnancy. Based on the injury profile in human and nonhuman primates, ZIKV entry into the fetal brain likely occurs across both the blood/cerebrospinal fluid barrier in the choroid plexus and the blood/brain barrier. ZIKV can also enter the eye by trafficking across the blood/retinal barrier. Ultimately, the efficient escape of innate immune defenses by ZIKV is a key factor leading to viral infection. However, the host immune response against ZIKV can lead to injury and perturbations in developmental programs that drive cellular division, migration, and brain growth. The combined effect of innate immune evasion to facilitate viral propagation and the maternal/placental/fetal immune response to control the infection will determine the extent to which ZIKV can injure the fetal brain.

Objective: To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals., Methods: SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system., Results: Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity ( EML1 , TUBB , KATNB1, CENPJ , GPSM2 )., Conclusion: This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia., Methods: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort., Results: The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria., Conclusion: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

Objectives: To elaborate the imaging phenotype associated with a homozygous c.743C > del frameshift mutation in DAG1 leading to complete absence of both α- and β-dystroglycan previously reported in a consanguineous Israeli-Arab family., Methods: We analyzed prenatal and postnatal imaging data of patients from a consanguineous Israeli-Arab kindred harboring the DAG1 mutation., Results: The imaging studies (fetal ultrasound, CT scan and postnatal MRI) demonstrated: flat cortex (abnormally thick with irregular pebbled cortical-white matter border on MRI), hydrocephalus, scattered small periventricular heterotopia and subependymal hemorrhages and calcifications, z-shaped brainstem, and in addition an occipital encephalocele, vermian agenesis, and an elongated and thick tectum (tectocerebellar dysraphia)., Conclusions: The novel association of cobblestone malformation with tectocerebellar dysraphia as part of WWS is characteristic of the homozygous c.743C > del frameshift mutation in the DAG1 gene., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41-52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndrome who had MRI scans of satisfactory quality were included. Of 55 patients, 34 (62%) demonstrated ≥1 non-vascular intracranial anomaly; structural brain malformations were present in 19 (35%). There was no difference in the prevalence of brain anomalies between genders. Brain anomalies were more likely in patients with S1 and/or S2 distribution of facial hemangioma. The most common structural brain defects were cerebellar hypoplasia (25%) and fourth ventricle abnormalities (13%). Dandy-Walker complex and malformations of cortical development were present in 9% and 7%, respectively. Extra-axial findings such as pituitary anomalies (18%) and intracranial hemangiomas (18%) were also observed. Six patients (11%) had anomalies of the globes or optic nerve/chiasm detectable on MRI. Brain malformations comprise a diverse group of structural developmental anomalies that are common in patients with PHACE syndrome. Along with brain malformations, numerous abnormalities of the pituitary, meninges, and globes were observed, highlighting the need for careful radiologic assessment of these structures in the neuroimaging workup for PHACE syndrome., (© 2017 Wiley Periodicals, Inc.)

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303&#95;Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303&#95;Leu2305dup) and p.(Arg2308&#95;Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined., Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations., Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis., Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

Objective: To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function., Methods: All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination., Results: Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI., Conclusions: Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling., (© 2017 American Academy of Neurology.)

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

Few systematic assessments of developmental forms of hydrocephalus exist. We reviewed magnetic resonance images (MRIs) and clinical records of patients with infancy-onset hydrocephalus. Among 411 infants, 236 had hydrocephalus with no recognizable extrinsic cause. These children were assigned to 1 of 5 subtypes and compared on the basis of clinical characteristics and developmental and surgical outcomes. At an average age of 5.3 years, 72% of children were walking independently and 87% could eat by mouth; in addition, 18% had epilepsy. Distinct patterns of associated malformations and syndromes were observed within each subtype. On average, children with aqueductal obstruction, cysts, and encephaloceles had worse clinical outcomes than those with other forms of developmental hydrocephalus. Overall, 53% of surgically treated patients experienced at least 1 shunt failure, but hydrocephalus associated with posterior fossa crowding required fewer shunt revisions. We conclude that each subtype of developmental hydrocephalus is associated with distinct clinical characteristics, syndromology, and outcomes, suggesting differences in underlying mechanisms., Competing Interests: Declaration of Conflicting Interests. No conflicts of interest have been identified by any of the authors or their collaborators., (© The Author(s) 2015.)

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The number of single genes associated with neurodevelopmental disorders has increased dramatically over the past decade. The identification of causative genes for these disorders is important to clinical outcome as it allows for accurate assessment of prognosis, genetic counseling, delineation of natural history, inclusion in clinical trials, and in some cases determines therapy. Clinicians face the challenge of correctly identifying neurodevelopmental phenotypes, recognizing syndromes, and prioritizing the best candidate genes for testing. However, there is no central repository of definitions for many phenotypes, leading to errors of diagnosis. Additionally, there is no system of levels of evidence linking genes to phenotypes, making it difficult for clinicians to know which genes are most strongly associated with a given condition. We have developed the Developmental Brain Disorders Database (DBDB: https://www.dbdb.urmc.rochester.edu/home), a publicly available, online-curated repository of genes, phenotypes, and syndromes associated with neurodevelopmental disorders. DBDB contains the first referenced ontology of developmental brain phenotypes, and uses a novel system of levels of evidence for gene-phenotype associations. It is intended to assist clinicians in arriving at the correct diagnosis, select the most appropriate genetic test for that phenotype, and improve the care of patients with developmental brain disorders. For researchers interested in the discovery of novel genes for developmental brain disorders, DBDB provides a well-curated source of important genes against which research sequencing results can be compared. Finally, DBDB allows novel observations about the landscape of the neurogenetics knowledge base., (© 2014 Wiley Periodicals, Inc.)

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.

Monosomy 1p36 is the most common subtelomeric chromosomal deletion linked to mental retardation and seizures. Neuroimaging studies suggest that monosomy 1p36 is associated with brain malformations including polymicrogyria and nodular heterotopia, but the histopathology of these lesions is unknown. Here we present postmortem neuropathological findings from a 10 year-old girl with monosomy 1p36, who died of respiratory complications. The findings included micrencephaly, periventricular nodular heterotopia in occipitotemporal lobes, cortical dysgenesis resembling polymicrogyria in dorsolateral frontal lobes, hippocampal malrotation, callosal hypoplasia, superiorly rotated cerebellum with small vermis, and lumbosacral hydromyelia. The abnormal cortex exhibited "festooned" (undulating) supragranular layers, but no significant fusion of the molecular layer. Deletion mapping demonstrated single copy loss of a contiguous 1p36 terminal region encompassing many important neurodevelopmental genes, among them four HES genes implicated in regulating neural stem cell differentiation, and TP73, a monoallelically expressed gene. Our results suggest that brain and spinal malformations in monosomy 1p36 may be more extensive than previously recognized, and may depend on the parental origin of deleted genes. More broadly, our results suggest that specific genetic disorders may cause distinct forms of cortical dysgenesis.

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome., (Copyright © 2013 Wiley Periodicals, Inc.)

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded by PRKDC) functions in DNA non-homologous end-joining (NHEJ), the major DNA double strand break (DSB) rejoining pathway. NHEJ also functions during lymphocyte development, joining V(D)J recombination intermediates during antigen receptor gene assembly. Here, we describe a patient with compound heterozygous mutations in PRKDC, low DNA-PKcs expression, barely detectable DNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system, we found that one of the PRKDC mutations inactivated DNA-PKcs, while the other resulted in dramatically diminished but detectable residual function. The patient suffered SCID with reduced or absent T and B cells, as predicted from PRKDC-deficient animal models. Unexpectedly, the patient was also dysmorphic; showed severe growth failure, microcephaly, and seizures; and had profound, globally impaired neurological function. MRI scans revealed microcephaly-associated cortical and hippocampal dysplasia and progressive atrophy over 2 years of life. These neurological features were markedly more severe than those observed in patients with deficiencies in other NHEJ proteins. Although loss of DNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronal development, our findings demonstrate a stringent requirement for DNA-PKcs during human neuronal development and suggest that high DNA-PK protein expression is required to sustain efficient pre- and postnatal neurogenesis.

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To describe a homogeneous subtype of periventricular nodular heterotopia (PNH) as part of a newly defined malformation complex., Methods: Observational study including review of brain MRI and clinical findings of a cohort of 50 patients with PNH in the temporo-occipital horns and trigones, mutation analysis of the FLNA gene, and anatomopathologic study of a fetal brain., Results: There were 28 females and 22 males. All were sporadic with the exception of an affected mother and son. Epilepsy occurred in 62%, cerebellar signs in 56%, cognitive impairment in 56%, and autism in 12%. Seventy percent were referred within the 3rd year of life. Imaging revealed a normal cerebral cortex in 76% and abnormal cortical folding in 24%. In all patients the hippocampi were under-rotated and in 10% they merged with the heterotopia. Cerebellar dysgenesis was observed in 84% and a hypoplastic corpus callosum in 60%. There was no gender bias or uneven gender distribution of clinical and anatomic severity. No mutations of FLNA occurred in 33 individuals examined. Heterotopia in the fetal brain revealed cytoarchitectonic characteristics similar to those associated with FLNA mutations; cortical pathology was not typical of polymicrogyria. Cerebellar involvement was more severe and the hippocampi appeared simple and under-rotated., Conclusions: This series delineates a malformation complex in which PNH in the trigones and occipito-temporal horns is associated with hippocampal, corpus callosum, and cerebellar dysgenesis. This subtype of PNH is distinct from classic PNH caused by FLNA mutations.

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Heterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia., Methods: The study characterised the CASK alteration in 20 new female patients by molecular karyotyping, fluorescence in situ hybridisation, sequencing, reverse transcriptase (RT) and/or quantitative real-time PCR. Clinical and brain imaging data of a total of 25 patients were reviewed., Results: 11 submicroscopic copy number alterations, including nine deletions of ~11 kb to 4.5 Mb and two duplications, all covering (part of) CASK, four splice, four nonsense, and one 1 bp deletion are reported. These heterozygous CASK mutations most likely lead to a null allele. Brain imaging consistently showed diffuse brainstem and cerebellar hypoplasia with a dilated fourth ventricle, but of remarkably varying degrees. Analysis of 20 patients in this study, and five previously reported patients, revealed a core clinical phenotype comprising severe developmental delay/intellectual disability, severe postnatal microcephaly, often associated with growth retardation, (axial) hypotonia with or without hypertonia of extremities, optic nerve hypoplasia, and/or other eye abnormalities. A recognisable facial phenotype emerged, including prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and/or large ears., Conclusions: These findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Microcephaly may be present at birth or develop postnatally. Classification according to the genetic cause cannot always predict the severity of the clinical course. The aim of this research was to group a large cohort of patients with primary microcephaly into more discrete subtypes, to optimize assessment of the patients based on their clinical and brain imaging findings. Medical records and brain images were reviewed for 4442 patients with brain malformations diagnosed and treated over 24 years and identified 247 patients classified as having microcephaly with simplified gyri alone or in association with additional brain abnormalities. For each case, clinical records were retrospectively reviewed for consanguinity, positive family history, sex, associated anomalies, and cranial magnetic resonance imaging. A subset (n = 12) of representative patients with the most complete available data was studied in greater detail, to define the most common subtypes and clinical presentations. Overall, four relatively common brain imaging presentations were identified, involving abnormalities in the gyral pattern, extra-axial space, and small size of the brainstem and cerebellum. Classifying patients with microcephaly according to brain imaging findings could enable more accurate counseling of the families with regard to prognosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring neurocutaneous disorder characterized by ocular anomalies, skin lesions, and CNS anomalies. We report on four new patients with this syndrome. Additionally, we reviewed (i) the brain imaging studies and clinical data of these new cases of ECCL and six other previously published ECCL patients, and (ii) the literature on 42 other patients who had undergone some form of neuroimaging, including three cases with probable or uncertain ECCL diagnoses. Thirty-three of 52 patients showed intracranial lipomas, frequently of cerebello-pontine location, and/or spinal lipomatosis. The latter has been found in 12/13 patients who had imaging studies of the spine. Other frequent findings included congenital anomalies of the meninges, in particular arachnoid cysts, and remarkably asymmetric anomalies caused by putative focal vascular defects, such as (partial) atrophy of one hemisphere or thin cerebral mantle, porencephalic cysts and calcifications. Vessel anomalies were found in nine patients. No correlation between the brain anomalies and the degree of retardation or epilepsy could be established. These data provide evidence that the brain anomalies in ECCL are not primary brain malformations but arise secondary to a mesenchymal defect affecting mostly neural crest derivatives., ((c) 2007 Wiley-Liss, Inc.)

The proposed new hominid "Homo floresiensis" is based on specimens from cave deposits on the Indonesian island Flores. The primary evidence, dated at approximately 18,000 y, is a skull and partial skeleton of a very small but dentally adult individual (LB1). Incomplete specimens are attributed to eight additional individuals. Stone tools at the site are also attributed to H. floresiensis. The discoverers interpreted H. floresiensis as an insular dwarf derived from Homo erectus, but others see LB1 as a small-bodied microcephalic Homo sapiens. Study of virtual endocasts, including LB1 and a European microcephalic, purportedly excluded microcephaly, but reconsideration reveals several problems. The cranial capacity of LB1 ( approximately 400 cc) is smaller than in any other known hominid < 3.5 Ma and is far too small to derive from Homo erectus by normal dwarfing. By contrast, some associated tools were generated with a prepared-core technique previously unknown for H. erectus, including bladelets otherwise associated exclusively with H. sapiens. The single European microcephalic skull used in comparing virtual endocasts was particularly unsuitable. The specimen was a cast, not the original skull (traced to Stuttgart), from a 10-year-old child with massive pathology. Moreover, the calotte does not fit well with the rest of the cast, probably being a later addition of unknown history. Consideration of various forms of human microcephaly and of two adult specimens indicates that LB1 could well be a microcephalic Homo sapiens. This is the most likely explanation for the incongruous association of a small-brained recent hominid with advanced stone tools., ((c) 2006 Wiley-Liss, Inc.)

Polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) are two developmental brain malformations that have been described independently in multiple syndromes. Clinically, they present with epilepsy and developmental handicaps in both children and adults. Here we describe their occurrence together as the two major findings in a group of at least three cortical malformation syndromes. We identified 30 patients as having both PNH and PMG on brain imaging, reviewed clinical data and brain imaging studies (or neuropathology summary) for all, and performed mutation analysis of FLNA in nine patients. The group was divided into three subtypes based on brain imaging findings. The frontal-perisylvian PNH-PMG subtype included eight patients (seven males and one female) between 2 days and 10 years of age. It was characterized by PNH lining the lateral body and frontal horns of the lateral ventricles and by PMG most severe in the posterior frontal and perisylvian areas, occasionally with extension to the parietal lobes beyond the immediate perisylvian cortex. The posterior PNH-PMG subtype consisted of 20 patients (15 male and 5 female) between 5 days and 40 years of age. It was characterized by PNH in the trigones, temporal and posterior horns of the lateral ventricles, and PMG most severe in the temporo-parieto-occipital regions. The third type was found in 2 females aged 7 months and 2 years, and was characterized by severe congenital microcephaly and more diffuse cortical abnormality. The PNH-PMG subtypes described here have distinct imaging and clinical phenotypes that suggest multiple genetic aetiologies involving defects in multiple genes, and a shared pathophysiological mechanism for PNH and PMG. The frontal-perisylvian and posterior subtypes both had skewing of the sex ratio towards males, which suggests the possibility of X-linked inheritance. Delineation of these syndromes will also aid in providing more accurate diagnosis and prognostic information for patients with these malformations.

Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type I) and cobblestone (type II). To date, mutations in 4 genes, LIS1, DCX, RELN, and ARX, have been associated with distinct type I lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS1 deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS1 deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS1. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for lissencephaly is proposed that incorporates both pathologic and genetic findings.

The most defining biological attribute of Homo sapiens is its enormous brain size and accompanying cognitive prowess. How this was achieved by means of genetic changes over the course of human evolution has fascinated biologists and the general public alike. Recent studies have shown that genes controlling brain development - notably those implicated in microcephaly (a congenital defect that is characterized by severely reduced brain size) - are favoured targets of natural selection during human evolution. We propose that genes that regulate brain size during development, such as microcephaly genes, are chief contributors in driving the evolutionary enlargement of the human brain. Based on the synthesis of recent studies, we propose a general methodological template for the genetic analysis of human evolution.

The Molar Tooth Sign (MTS) is defined by an abnormally deep interpeduncular fossa; elongated, thick, and mal-oriented superior cerebellar peduncles; and absent or hypoplastic cerebellar vermis that together give the appearance of a "molar tooth" on axial brain MRI through the junction of the midbrain and hindbrain (isthmus region). It was first described in Joubert syndrome (JS) where it is present in the vast majority of patients with this diagnosis. We previously showed that the MTS is a component of several other syndromes, including Dekaban-Arima (DAS), Senior-Löken, and COACH (cerebellar vermis hypoplasia (CVH), oligophrenia, ataxia, coloboma, and hepatic fibrosis). Here we present evidence that the MTS is seen together with polymicrogyria, Váradi-Papp syndrome (Orofaciodigital VI (OFD VI)), and a new syndrome with encephalocele and cortical renal cysts. We also present a new patient with COACH syndrome plus the MTS. We propose that the MTS is found in multiple distinct clinical syndromes that may share common developmental mechanisms. Proper classification of patients with these variants of the MTS will be essential for localization and identification of mutant genes., (Copyright 2003 Wiley-Liss, Inc.)

Regional skin hypoplasia has been described in several genetic syndromes, including focal dermal hypoplasia (FDH), microphthalmia with linear skin defects (MLS), oculocerebrocutaneous syndrome (OCCS), and terminal osseous dysplasia and pigmentary defects (TODP). All but OCCS have been reported to follow an X-linked inheritance pattern. We describe a 14-year-old girl with clinical features overlapping with these disorders. She had mild mental retardation, macrocephaly, microphthalmia, right-sided morning glory optic disc anomaly, palmar and lip pits, and polysyndactyly. A swirling pattern of skin hypopigmentation, papular hypopigmented and herniated skin lesions reminiscent of FDH most prominent over her face, head, hands, and feet was evident. Brain magnetic resonance imaging (MRI) showed polymicrogyria (most severely in the perisylvian and mesial frontal regions), enlarged left lateral ventricle, partial agenesis of the corpus callosum, and optic nerve tumor on the right. Dermatopathologic examination of the skin lesions was consistent with basaloid follicular hamartomas. The skin and digit anomalies observed overlap with FDH, but polymicrogyria, basaloid follicular hamartomas, optic nerve tumor, and morning glory anomaly have not previously been described in FDH. Skin defects in MLS are linear and the eyes typically have sclerocornea. Polymicrogyria has been described in OCCS, but not in any of the other three syndromes. The limb anomalies in TODP are reductions rather than polysyndactyly. Skin defects are localized to the face, and digital fibromas usually occur. While significant overlap exists between all four of the syndromes discussed, we believe that the constellation of anomalies observed in this girl most likely comprises a newly recognized syndrome., (Copyright 2003 Wiley-Liss, Inc.)

Classical lissencephaly (LIS) and subcortical band heterotopia (SBH) are related cortical malformations secondary to abnormal migration of neurons during early brain development. Approximately 60% of patients with classical LIS, and one patient with atypical SBH have been found to have deletions or mutations of the LIS1 gene, located on 17p13.3. This gene encodes the LIS1 or PAFAH1B1 protein with a coiled-coil domain at the N-terminus and seven WD40 repeats at the C-terminus. It is highly conserved between species and has been shown to interact with multiple proteins involved with cytoskeletal dynamics, playing a role in both cellular division and motility, as well as the regulation of brain levels of platelet activating factor. Here we report 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including four not previously reported, the majority of which have been found as a consequence of the investigation of 220 children with LIS or SBH by our group. All intragenic mutations are de novo, and there have been no familial recurrences. Eight-eight percent (36/41) of the mutations result in a truncated or internally deleted protein-with missense mutations found in only 12% (5/41) thus far. Mutations occurred throughout the gene except for exon 7, with clustering of three of the five missense mutations in exon 6. Only five intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations., (Copyright 2001 Wiley-Liss, Inc.)

We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic "butterfly"-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term "diencephalic-mesencephalic junction dysplasia" to characterize this autosomal recessive malformation.

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology. [ABSTRACT FROM AUTHOR]