A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.

Bilateral perisylvian polymicrogyria (BPP) is a structural malformation of the cerebral cortex that can be caused by several genetic abnormalities. The most common clinical manifestations of BPP include intellectual disability and epilepsy. Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a protein that interacts with the fragile X mental retardation protein (FMRP). CYFIP2 variants can cause various brain structural abnormalities with the most common clinical manifestations of intellectual disability, epileptic encephalopathy and dysmorphic features. We present a girl with multiple disabilities and BPP caused by a heterozygous, novel, likely pathogenic variant (c.1651G>C: p.(Val551Leu) in the CYFIP2 gene. Our case report broadens the spectrum of genetic diversity associated with BPP by incorporating CYFIP2.

Cilostazol treats transient heart failure caused by ATP1A3 variant-associated polymicrogyria.

BACKGROUND: Some patients with ATP1A3 variant-associated polymicrogyria have recurrent transient heart failure. However, effective treatment for the transient cardiac condition remains to be elucidated. CASE REPORT: The patient started experiencing focal motor onset seizures in 12 h after birth, revealing bilateral diffuse polymicrogyria. The patient also experienced transient bradycardia (sinus bradycardia) attacks from 15 days old. Echocardiography revealed a reduced ejection fraction; however, no obvious electrocorticogram or electroencephalogram abnormalities were observed during the attacks. Initially, the attacks occurred in clusters daily. They later decreased in frequency, occurring at monthly intervals. Repeated episodes of transient bradycardia attacks and polymicrogyria indicated possible ATP1A3 gene abnormality and genetic testing revealed a novel heterozygous ATP1A3 variant (NM_152296: exon22:c.2977_2982del:p.(Glu993_Ile994del)), which was not found in the patient's parents. Cilostazol was administered at 3 months old for recurrent transient bradycardia attacks. Cilostazol significantly shortened the duration of bradycardia episodes and prolonged the interval between attacks. Cilostazol also effectively treats transient symptomatic bradycardia. CONCLUSION: Cilostazol could be a treatment option for recurrent transient bradycardia attacks associated with ATP1A3 gene abnormalities and polymicrogyria.

Prenatal Ultrasound Diagnosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome with Persistent Hyperplastic Primary Vitreous: A Case Report.

INTRODUCTION: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare autosomal dominant disorder characterized by megalencephaly (i.e., overgrowth of the brain), polymicrogyria, focal hypoplasia of the cerebral cortex, and polydactyly. Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities that are characterized by the presence of a vascular membrane behind the lens. CASE PRESENTATION: Here, we present a case of foetal MPPH with PHPV that was diagnosed using prenatal ultrasound. Ultrasound revealed the presence of megalencephaly, multiple cerebellar gyri, and hydrocephalus. Whole-exome sequencing confirmed the mutation of the AKT3 gene, which led to the consideration of MPPH syndrome. Moreover, an echogenic band with an irregular surface was observed between the lens and the posterior wall of the left eye; therefore, MPPH with PHPV was suspected. CONCLUSION: MPPH syndrome with PHPV can be diagnosed prenatally.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia.

BACKGROUND: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. METHODS: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. RESULTS: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. CONCLUSIONS: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.

Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases. Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations. Design, Setting, and Participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control. Main Outcomes and Measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed. Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families. Conclusions and Relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

COL4A1 mutation-related disorder presenting as fetal intracranial bleeding, hydrocephalus, and polymicrogyria.

Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial hemorrhage and ventriculomegaly carrying a novel, previously unreported, likely pathogenic variant in COL4A1. At the gestational age of 27 weeks, dilation of lateral ventricles was detected during a routine prenatal ultrasound scan, confirmed by prenatal MRI at 30 + 3 weeks of gestation. Prenatal examinations included amniocentesis with conventional G-band karyotyping and arrayCGH, and maternal testing for TORCH and parvovirus B19 infections. Virtual gene panel based on whole-exome sequencing data was performed postnatally. At the age of 2.5 months, the patient manifested epileptic seizures that remain difficult to control. Postnatal MRI showed partial thalamic fusion and polymicrogyria, in addition to severe enlargement of lateral ventricles, multiple deposits of hemosiderin in cerebral and cerebellar hemispheres, and thin optic nerve and chiasma. Virtual gene panel based on whole-exome sequencing data led to a detection of a de novo previously unreported in-frame deletion NM_001845.5:c.4688_4711del in COL4A1 located in the highly conserved NC1 domain initiating collagen helix assembly. The presented case lies one a more severe end of the COL4A1 mutation-related disease spectrum, manifesting as fetal intracranial bleeding, malformation of cortical development, drug-resistant epilepsy, and developmental delay.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

Hemidystonia with polymicrogyria is part of ATP1A3-related disorders.

INTRODUCTION: Pathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3-related disorders. CASE REPORT: We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant. CONCLUSION: This case expands the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition.

[Analysis of clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion].

Objective: To investigate the clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion. Methods: The patients (n=10) with 16p11.2 microdeletion found in children with epilepsy treated in Beijing Children's Hospital Affiliated to Capital Medical University from January 2018 to January 2021 were collected. The clinical manifestations, gene variations and prognosis were analyzed retrospectively. Results: A total of 10 children's data were collected, including 5 male and 5 female. The onset age of epilepsy was 4.5 (4.1,5.0) months. Regarding the seizure types, 7 cases had focal seizures with secondary generalization, 2 cases had generalized seizures, and 1 case had tonic seizures and spasms. Nine cases had cluster seizure attacks and 3 cases had status epilepticus. Seven cases had focal or multifocal epileptiform discharges in interictal electroencephalogram (EEG), 3 cases had borderline or normal EEG. Brain magnetic resonance imaging showed polymicrogyria in 1 case, paraventricular leukomalacia in 1 case, delayed myelination of white matter in 3 cases, and no obvious abnormalities in the other 5 cases. The patients were followed up for 0.5-3.5 years, with 1-3 kinds of antiepileptic drugs taken orally. The case with polymicrogyria still had seizures, however the other 9 cases had seizures controlled. The age of the last seizure attack was 8 (6, 12) months. There were 6 cases with mental and motor developmental delay before epilepsy onset. During the follow-up, 7 cases were retarded to varying degrees, while 3 cases had normal development. Regarding the genetic detection methods, 7 cases underwent whole exome sequencing, 2 cases underwent whole genome copy number variation detection, and 1 case underwent whole genome sequencing. The length of the 16p11.2 deletion in 10 cases ranged from 525 to 951 kb, and all contained the PRRT2 gene intact. Six cases were de novo variants, 1 case was inherited from the mother who had a history of convulsions in early childhood, and the source of variant was not verified in 3 cases, none of whose parents had relevant phenotype. Conclusions: The epilepsy associated with 16p11.2 microdeletion is mainly induced by the heterozygous deletion of PRRT2 gene in this region, however the phenotype is usually severe, and often combined with developmental and epileptic encephalopathy. Detection of copy number variation should be emphasized in children whose etiology is considered genetic but second-generation sequencing result is negative.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders.

OBJECTIVE: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations. METHODS AND RESULTS: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development. CONCLUSIONS: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.

Polymicrogyria in a child with KCNMA1-related channelopathy.

BACK GROUND: Polymicrogyria is a malformation of cortical development with overfolding of the cerebral cortex and abnormal cortical layering. Polymicrogyria constitutes a heterogenous collection of neuroimaging features, neuropathological findings, and clinical associations, and is due to multiple underlying etiologies. In the last few years, some glutamate and sodium channelopathies have been associated with cortical brain malformations such as polymicrogyria. The potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) gene encodes each of the four alpha-subunits that make up the large conductance calcium and voltage-activated potassium channel "Big K+". KCNMA1-related channelopathies are associated with various neurological abnormalities, including epilepsy, ataxia, paroxysmal dyskinesias, developmental delay and cognitive disorders. CASE REPORT: We report the observation of a patient who presented since the age of two months with drug-resistant epilepsy with severe developmental delay initially related to bilateral asymmetric frontal polymicrogyria. Later, exome sequencing revealed a de novo heterozygous variation in the KCNMA1 gene (c.112delG) considered pathogenic. CONCLUSION: This first case of polymicrogyria associated with KCNMA1-related channelopathy may expand the phenotypic spectrum of KCNMA1-related channelopathies and enrich the recently identified group of developmental channelopathies with polymicrogyria.

A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria.

Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2, a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2−GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria.

Analysis of clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion / 中华儿科杂志

Objective: To investigate the clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion. Methods: The patients (n=10) with 16p11.2 microdeletion found in children with epilepsy treated in Beijing Children's Hospital Affiliated to Capital Medical University from January 2018 to January 2021 were collected. The clinical manifestations, gene variations and prognosis were analyzed retrospectively. Results: A total of 10 children's data were collected, including 5 male and 5 female. The onset age of epilepsy was 4.5 (4.1,5.0) months. Regarding the seizure types, 7 cases had focal seizures with secondary generalization, 2 cases had generalized seizures, and 1 case had tonic seizures and spasms. Nine cases had cluster seizure attacks and 3 cases had status epilepticus. Seven cases had focal or multifocal epileptiform discharges in interictal electroencephalogram (EEG), 3 cases had borderline or normal EEG. Brain magnetic resonance imaging showed polymicrogyria in 1 case, paraventricular leukomalacia in 1 case, delayed myelination of white matter in 3 cases, and no obvious abnormalities in the other 5 cases. The patients were followed up for 0.5-3.5 years, with 1-3 kinds of antiepileptic drugs taken orally. The case with polymicrogyria still had seizures, however the other 9 cases had seizures controlled. The age of the last seizure attack was 8 (6, 12) months. There were 6 cases with mental and motor developmental delay before epilepsy onset. During the follow-up, 7 cases were retarded to varying degrees, while 3 cases had normal development. Regarding the genetic detection methods, 7 cases underwent whole exome sequencing, 2 cases underwent whole genome copy number variation detection, and 1 case underwent whole genome sequencing. The length of the 16p11.2 deletion in 10 cases ranged from 525 to 951 kb, and all contained the PRRT2 gene intact. Six cases were de novo variants, 1 case was inherited from the mother who had a history of convulsions in early childhood, and the source of variant was not verified in 3 cases, none of whose parents had relevant phenotype. Conclusions: The epilepsy associated with 16p11.2 microdeletion is mainly induced by the heterozygous deletion of PRRT2 gene in this region, however the phenotype is usually severe, and often combined with developmental and epileptic encephalopathy. Detection of copy number variation should be emphasized in children whose etiology is considered genetic but second-generation sequencing result is negative.

Autism spectrum disorder in a child with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP).

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is a rare disorder that arises as a result of a somatic mosaic mutation in the PIK3CA gene. It characteristically presents with postnatal or congenital megalencephaly, cutaneous capillary malformations, postaxial polydactyly and often segmental or focal body overgrowth. We report a 7-year-old boy with known MCAP who was diagnosed at around 10 months old with a mosaic change in the PIK3CA gene. He was found to have hall-mark clinical signs; macrocephaly and four-limb postaxial polydactyly. Since diagnosis, he has had multiple clinical features, most of which typically present in children with MCAP. He has now been diagnosed with autism spectrum disorder (ASD), demand avoidance and is under assessment for attention deficit hyperactivity disorder. Although some cases have been raised to the M-CM Network, to our knowledge this is the first case of ASD in MCAP to be reported in the literature.

CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum.

Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome.

Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.

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.