Digital Anomalies Research Articles

Challenges and Strategies for Community Elderly Care Services in the Era of Digital Governance

With our country's technological advancements, digital governance is increasingly penetrating all aspects of social life, particularly in the public service sector. As the "silver-haired group" grows, so does the demand for and attention to community elderly care services. The introduction of digital governance offers new opportunities in this field, yet it presents significant challenges. The integration of intelligent technology in community elderly care, facilitated by digital advancements, enhances service efficiency and quality, enabling more convenient and personalized care for the elderly. However, the implementation faces specific challenges: digital anomalies where technology usage exceeds conventional norms, a digital divide marked by the elderly's limited ability to utilize new intelligent devices and services, and insufficient professional training for caregivers. These issues complicate the promotion of digital governance in elderly care services. Addressing these problems involves several strategic measures: refining systems to bridge the digital divide, enhancing the training and familiarity of digital technologies among the elderly, and improving caregiver professionalism. Additionally, establishing robust data security management and privacy protection mechanisms, along with advancing the legal framework surrounding eldercare, are crucial. Moreover, it is vital to provide more emotional care, enhance the elderly's sense of belonging, and meet their emotional needs to support the effective integration of digital governance into community elderly care services.

Biallelic loss of function variants in FUZ result in an orofaciodigital syndrome

Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding the CPLANE complex result in a wide variety of skeletal dysplasia with disturbed ciliary functions. The phenotypic spectrum includes orofaciodigital syndrome and short rib polydactyly syndrome. FUZ, as a part of the CPLANE complex, is involved in intraflagellar vesicular trafficking within primary cilia. Previously, the variants, c.98_111+9del and c.851G>T in FUZ were identified in two individuals with a skeletal ciliopathy, manifesting digital anomalies (polydactyly, syndactyly), orofacial cleft, short ribs and cardiac defects. Here, we present two novel variants, c.601G>A and c.625_636del in biallelic state, in two additional subjects exhibiting phenotypic overlap with the previously reported cases. Our findings underscore the association between biallelic loss of function variants in FUZ and skeletal ciliopathy akin to orofaciodigital syndrome.

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review

BackgroundTRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations. MethodsWe present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one. ResultsPhenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas. ConclusionsOur comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7-related CAFDADD, offering insights for improved diagnosis, intervention, and patient care.

ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet

BackgroundResearch has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring. MethodsThe clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature. ResultsThe infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD). ConclusionCHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.

ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals.

Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as PIG and PGAP genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. PGAP2 stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in PGAP2 in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with PGAP2 variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with PGAP2 variants.

Clinico-radiological findings in Stoneman disease

Myositis ossificans progressive/fibrodysplasia ossificans progressiva (FOP) or stone man disease, is a rare autosomal dominant connective tissue disorder characterized by progressive ectopic ossification of soft tissues. This disorder affects approximately one in two million individuals, with an autosomal dominant inheritance pattern. Most cases, however, occur sporadically within families. FOP manifests as gradual ossification of connective tissues and muscles, presenting with digital anomalies and additional features such as neck muscle edema, C2-C7 facet joint fusion, and enlarged vertebrae. We present the case of a 8-year-old boy with FOP, showcasing distinctive clinical and radiological features. The patient experienced a gradually hardening swelling and progressive limitation of movement along the back over six years. Clinical examination revealed bilateral hallux valgus with short great toes, and radiographic studies confirmed characteristic findings, including elongated ectopic osseous growths in the spine and deformities in the feet. Diagnostic imaging, including plain radiographs and CT scans, plays a crucial role in confirming FOP and assessing its extent. Characteristic findings such as deformed great toes, ectopic calcifications, and osseous bridging are evident. Early detection through bone scans or MRI is crucial for timely intervention. However, biopsies are discouraged due to the risk of exacerbating ossification and potential confusion with malignancies. Current therapeutic interventions are primarily supportive, as surgical procedures carry risks of trauma-induced ossification. Preventive measures, including lifestyle modifications and avoiding trauma, are key. Medications like bisphosphonates and corticosteroids may be considered during acute flare-ups, but research for definitive treatment is ongoing. FOP poses significant challenges in diagnosis, management, and treatment due to its rarity and variable clinical course. Early recognition, thorough clinical assessments, and a proactive approach to prevention are crucial for enhancing the quality of life for individuals with FOP. Ongoing research aims to uncover more effective treatments, while support groups and patient education contribute to a comprehensive approach in addressing this complex disorder.

Algorithmic means of ensuring network security and websites: trends, models, future cases

The purpose of the study is to establish probable trends in the development of algorithmic means of network security and the protection of web resources in the future. The research methods used in this publication are a bibliometric analysis of 500 relevant publications, which allowed us to establish probable trends in the future development of the subject field. The study found that currently the most likely algorithmic means of network security and website protection that will be intensively developed in the future are blockchain technologies (to protect inter-resource contact), deep and machine learning (to analyze and detect attacks and digital anomalies), artificial intelligence and neural networks (to develop complex security algorithms), and predictive analysis (to prevent possible attacks and malicious data injections). At the same time, technological development makes it possible to identify alternative security tools, including quantum and post-quantum cryptography (which is possible due to the development of quantum computing), augmented reality (which is the next iteration of the development of the interface between machine-human interaction), biometric identification (which is the next iteration of authentication and recognition systems) and DevSecOps (which is a promising technology for the production of digital tools and systems that have a relatively lower level of vulnerability to known digital threats). The correlative impact of Industry 4.0 technologies and solutions on the studied aspects of the security sector of the World Wide Web has been established. The growth of the network of devices requires the improvement of security algorithms in the paradigm of Industry 4.0 technologies, which will allow more effective detection and prevention of cyberattacks and protection of user data.

Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.

Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over twenty genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families. Affected individuals presented a novel form of OFDS (OFDS-RAB34) accompanied by cardiac, cerebral, skeletal, and anorectal defects. RAB34 encodes a member of the Rab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Unlike many genes required for cilium assembly, RAB34 acts selectively in cell types that use the intracellular ciliogenesis pathway, in which nascent cilia begin to form in the cytoplasm. We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function. Although some variants retain the ability to be recruited to the mother centriole, cells expressing mutant RAB34 exhibit a significant defect in cilium assembly. While many Rab proteins have been previously linked to ciliogenesis, our studies establish RAB34 as the first small GTPase involved in OFDS and reveal the distinct clinical manifestations caused by impairment of intracellular ciliogenesis.

Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired invitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles thannull alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Maternal Cigarette Smoking and Congenital Upper and Lower Limb Differences: A Systematic Review and Meta-Analysis.

Maternal smoking during pregnancy has been associated with adverse effects on foetal development, including congenital limb anomalies. This systematic review aimed to provide an updated assessment of the association between maternal smoking during pregnancy and the risk of congenital limb anomalies. A systematic search was conducted to identify relevant studies published up to February 2023. Studies reporting on the relationship between maternal smoking during pregnancy and congenital digital anomalies or congenital limb reduction defects were included. Two independent reviewers screened the studies, extracted data, and assessed the quality of the included studies. Meta-analyses were performed to estimate the pooled odds ratios with 95% confidence intervals using fixed and random-effects models. In total, 37 publications comprising 11 cohort and 26 case-control studies were included in the systematic review. The meta-analysis demonstrated a significant increased risk of congenital limb reduction defects (pooled OR: 1.27, 95% CI: 1.18-1.38) in infants born to mothers who smoked during pregnancy. Similarly, a significant relationship was observed for the development of polydactyly/syndactyly/adactyly when considered as a single group (pooled OR: 1.32, 95% CI: 1.25-1.40). Yet, in contrast, no significant association was observed when polydactyly (pooled OR: 1.06, 95% CI: 0.88-1.27) or syndactyly (pooled OR: 0.91, 95% CI: 0.77-1.08) were considered individually. This systematic review provides updated evidence of a significant relationship between maternal smoking during pregnancy and increased risk of congenital limb anomalies. These findings highlight the potential detrimental effects of smoking on foetal limb development and underscore the importance of smoking cessation interventions for pregnant women to mitigate these risks.

A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

RAS genes (HRAS, KRAS, and NRAS) are commonly mutated genes in cancer, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical NGS-based testing. We investigated the mutational spectrum and genotype-phenotype associations of mosaic RAS variants. Here we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Further, we present 12 individuals with HRAS and KRAS in-frame duplications/insertions (dup/ins) variants in the switch II domain. Among the 18.3% of individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations. The median age at testing for individuals with in-frame dup/ins variants was older, and the variant allele fraction was lower compared to those with mosaic RAS hotspots. Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in non-malignant conditions.

AMOTL1 De Novo Mutation Associated with Orofacial Clefting, Ocular Colobomas, an Atrial Septal Defect and Digital Anomalies: A Case Report and Review of the Literature

AMOTL1 De Novo Mutation Associated with Orofacial Clefting, Ocular Colobomas, an Atrial Septal Defect and Digital Anomalies: A Case Report and Review of the Literature

25. Genetic spectrum of RAS Alterations-A Highlight of in-frame insertion variants in association with vascular anomalies

RAS genes constitute a multigene family that includes HRAS, NRAS, and KRAS. Activated variants in RAS genes, occurring at hotspots including Gly12, Gly13, and Gln61, have been found in a wide variety of tumor types. Those hotspots have also been described in disorders of somatic mosaicism (DoSM), including vascular tumors, vascular malformations, nevus syndrome, segmental overgrowth, and digital anomalies. Here, we review a cohort of 938 individuals with DoSM and identified 64 cases with pathogenic (P) and likely pathogenic (LP) variants in the RAS genes, including 37 cases in the KRAS gene, 18 in the HRAS gene, and 9 in the NRAS gene. Unlike the recurrent hotspots, 10 of the 64 cases (15.6%) carried an in-frame insertion P/LP variant in either KRAS (n=4) or HRAS (n=6). In-frame insertion variants in HRAS and KRAS have not been observed in cancer databases. Only a few similar KRAS in-frame insertions in tumor samples have been previously published. Functional studies have shown that in-frame RAS insertions in the switch II region weakly increase RAS signaling via a decrease in intrinsic GTPase activity. Germline, in-frame insertion HRAS variants have been observed in Costello syndrome patients with milder phenotypes. Comparably, individuals with in-frame insertion HRAS and KRAS variants in this study had milder phenotypes compared to those with missense RAS variants. This study has reviewed the genetic spectrum of RAS gene alterations in a large cohort of cases with DoSM, highlighting the unique group of in-frame insertion variants in association with vascular malformation.

INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex

Oral-facial-digital (OFD) syndromes are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. Mutations within 12 cilia-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline variants in INTS13, a subunit of the Integrator complex. This multiprotein complex associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. We determined that INTS13 utilizes its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline variants p.S652L and p.K668Nfs*9. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos leads to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions between components of the Integrator complex.

Digital elevation model and satellite gravity anomalies and its correlation with geologic structures at Borena basin, in the Southern Main Ethiopian Rift

ABSTRACT This study integrates remote sensing data via Digital Elevation Model (DEM) and satellite gravity data to detect geologic structurs at Borena and the surrounding regions in the Southern Main Ethiopia Rift (SMER). Shading from different sun azimuths with 45-degree intervals and the tilt angle method was used to map lineaments and detect edges of anomalies from the DEM and gravity data, respectively. The area’s geology comprises quaternary alluvial and eluvial sediments , pre-rift and rift volcanic rock , and Precambrian banded gneiss. The Ririba, Mega and Chew Bahir rift systems make the main structural fabric of the area. About 793 lineaments from DEM data and 441 from gravity data were outlined, and their orientations were analyzed using rose diagrams. These are trending dominantly in NW to SE and N to S directions. From the gravity data analysis, the depth of anomalies ranges from 300 m to more than 7 km below the ground, with most of the lineaments being at shallow depth. The results obtained agree with the main tectonic features found in the study area. The integration of remote sensing data has facilitated delineating structural features in studying the regional geology of the large area.

Whole-Exon Sequencing and Correlation Analysis of a 14-Month-Old Girl With Orofaciodigital Syndrome.

Orofaciodigital syndrome type 1 (OFDS1) is a genetic disorder characterized by specific oral, facial, and limb malformations. A 14-month-old girl with congenital cleft palate, lower lip midline cleft, and digital anomalies admitted to our hospital was preliminarily diagnosed with OFDS1. Genetic analysis revealed that she carried a heterozygous variant of OFD1 at locus Xp22.2 on the X chromosome. Herein, we present the specific phenotype and genotype and the treatment modalities for this patient and references for diagnosing and treating OFDS.

Fast computation of digital terrain model anomalies based on LiDAR data for geoglyph detection in the Amazon

ABSTRACT The detection of pre-Colombian geoglyphs, geometric structures outlined by trenches or walls, from airborne LiDAR data is usually made by visual observation of the variation in elevation and commonly using additional hillshading. Depending on the area covered by LiDAR to inspect and the variation in elevation, this method can be time consuming and inaccurate as it required to constantly adjust the contrasts of the elevation image or the parameter of the hillshading function, and the user can miss some important archaeological features. Here, we present a method to enhance the anomaly of the terrain without using focal operations to normalize the elevation of each pixel in relation to its neighbours. An example is given for two areas covered by LiDAR and containing geoglyphs under the forest cover in the Amazon and with a synthetic LiDAR footprint over a simulated dense forested area containing four geoglyphs with different shapes and height/depth characteristics. The normalization enables to remove the influence of the landscape mean elevation, to highlight the fine anomaly of the terrain. The produced equalized images enable a fast visual assessment of relief anomaly and of the presence of geoglyphs in large LiDAR datasets of hundreds or thousands of LAS files.

EP097: The utility of CSF-derived cell free DNA in molecular diagnostics for the Megalencephaly-capillary Malformation (MCAP) syndrome: A case report

The Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome caused by mosaic gain-of-function (activating) variants in the PIK3CA gene. This multi-system disorder is characterized by megalencephaly (MEG) or hemimegalencaphly (HMEG), cutaneous vascular malformations, variable somatic overgrowth, digital anomalies, and connective tissue laxity. Epilepsy is commonly associated with MCAP, and a subset of affected individuals have cortical malformations which may require resective epilepsy surgery.