Perinatalna opieka paliatywna realizowana w oddziale polozniczym i neonatologicznym we wspólpracy z hospicjum dla dzieci - doswiadczenia wlasne.

INTRODUCTION: Wady letalne prowadza do wewnatrzmacicznego zgonu plodu lub dziecka bezposrednio po urodzeniu lub we wczesnym okresie niemowlecym, bez wzgledu na zastosowane leczenie. W przypadku wad letalnych nie ma mozliwosci skutecznej pomocy dziecku, mimo postepu mi zeadsytcoysnoyw ania najnowoczesniejszej aparatury lub terapii. Rodzice, którzy decyduja sie na urodzenie dziecka z wada letalna moga byc objeci perinatalna opieka hospicyjna, która ma charakter kompleksowy. Polega ona na wsparciu ciezarnej w okresie przygotowania do porodu, w czasie porodu i po porodzie oraz na wsparciu jej rodziny oraz obejmuje udzielenie rodzicom pelnej informacji o chorobie ich dziecka. Opieka nad dzieckiem po urodzeniu jest nastawiona na ochrone przed uporczywa terapia i zapewnienie dziecku opieki paliatywnej. CEL: Wykazanie znaczenia perinatalnej opieki paliatywnej dla kobiet w ciazy, u których wyniki badan prenatalnych wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu oraz przedstawienie schematu postepowania wedlug modelu wewnatrzszpitalnego hospicjum perinatalnego. MATERIAL I METODY: Analiza retrospektywna objeto dokumentacje 67 pacjentek skierowanych do Programu RAZEM we Wroclawiu w latach 2014-2018 z powodu nieprawidlowych wyników badan prenatalnych (ultrasonograficznych lub/i genetycznych), które wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Dokonanoanalizy danych socjodemograficznych, danych klinicznych rozpoznania choroby u plodu, przebiegu ciazy i porodu, trybu postepowania w okresie prenatalnym, podczas porodu i po urodzeniu sie dziecka. WYNIKI: Do Programu zostalo skierowanych 67 kobiet w wieku 20-43 lat (srednio 31,2), które zglaszaly sie w okresie od 15 do 39 tygodnia ciazy (srednio w 25. tygodniu ciazy). Do opieki paliatywnej zakwalifikowano 57 kobiet, czyli 85% skierowanych do programu. Opieke paliatywna kontynuowano u 51 pacjentek, poniewaz 6 kobiet w trakcie procesu diagnostycznego zdecydowalo sie na zakonczenie ciazy (10,5%). Najczestszymi zaburzeniami u plodów byly aberracje chromosomowe, wady OUN i wady nerek. W 95% przypadków doszlo do obumarcia wewnatrzmacicznego plodu lub smierci noworodka. WNIOSKI: Perinatalna opieka paliatywna jest niezbedna forma opieki dla kobiet w ciazy, u których wyniki badan prenatalnych wskazuja na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Model wewnatrzszpitalny hospicjum perinatalnego jest korzystna forma opieki, zapewnia jej spójnosc i dobra komunikacje w zespole, co wplywa na dobra jakosc opieki. INTRODUCTION: Lethal defects lead to the intrauterine death of the fetus or the passing away of the child immediately after birth or in early infancy, regardless of the treatment used. In the case of lethal defects, it is not possible to effectively help the child, despite using the most modern equipment or medicines in the treatment or the progress made by medicine. Parents, who decide to continue the pregnancy, although the fetus has a lethal defect that cannot be cured, may be covered by perinatal hospice care, which is comprehensive and consists in supporting the pregnant woman during the prenatal time, during delivery and after delivery and support of her family, giving full information to the parents about their child's illness. Childcare after birth is focused on protecting the infant from persistent therapy and providing him with appropriate conditions. AIM: To demonstrate the role of perinatal palliative care for pregnant women in whom the results of prenatal tests pointed to a severe developmental disorder in the fetus with a potentially lethal prognosis, and to present a pattern of behavior for their hospitalization in the perinatal hospice. MATERIALS AND METHODS: The retrospective analysis included documentation of 67 patients referred to the RAZEM (TOGETHER) Program in Wroclaw in 2014-2018 due to abnormal results of (ultrasound and / or genetic) prenatal tests, which indicated a serious developmental disorder in the fetus with potentially lethal prognosis. Analysis was conducted of sociodemographic data, clinical data on fetal diagnosis, pregnancy and delivery, the procedure for prenatal delivery and postnatal birth. RESULTS: 67 women aged 20-43 years (mean 31.2) were referred to the RAZEM Program. Out of these, 57 women were enrolled for palliative care, which accounted for 85% of those referred to the program. Palliative care was continued in 51 patients, because 6 women decided to terminate their pregnancy during the diagnostic process (10.5%). The most common abnormalities in the fetuses were chromosomal aberrations, CNS defects and kidney defects. In 95% of the cases, intrauterine fetal death or neonatal death occurred. CONCLUSIONS: Perinatal palliative care is an indispensable form of care for pregnant women in whom the results of prenatal tests indicate a serious developmental disorder in the fetus with potentially lethal prognosis. The in-hospital model of a perinatal hospice is a beneficial form of care, as it ensures consistency and good communication in the team, which favourably affects its quality.

Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene.

PIEZO2 protein is a unique ion channel that converts mechanical impulses into cellular signals in somatosensory neurons and is involved in various mechanotransduction pathways. The recessive PIEZO2 loss-of-function pathogenic variants are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT). Here we present three new DAIPT patients. The genetic diagnosis was established by exome sequencing and let us to identify 6 novel loss-of-function PIEZO2 variants: four splicing (c.1080+1G>A, c.4092+1G>T, c.6355+1G>T, and c.7613+1G>A), one nonsense (c.6088C>T) and one frameshift variant (c.6175_6191del) for which mosaic variant was identified in proband's mother. All patients presented typical symptoms at birth, with congenital contractures, bilateral hip dislocation/dysplasia, generalized hypotonia, transient feeding and difficulties. Two were afflicted by transient respiratory insufficiency. In all children motor development was severely delayed. In one patient, severe cognitive delay was also observed. Moreover, among the cases described by us there is the youngest diagnosed child to date.

Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine.

Over the last decades, transcriptome profiling emerged as one of the most powerful approaches in oncology, providing prognostic and predictive utility for cancer management. The development of novel technologies, such as revolutionary next-generation sequencing, enables the identification of cancer biomarkers, gene signatures, and their aberrant expression affecting oncogenesis, as well as the discovery of molecular targets for anticancer therapies. Transcriptomics contribute to a change in the holistic understanding of cancer, from histopathological and organic to molecular classifications, opening a more personalized perspective for tumor diagnostics and therapy. The further advancement on transcriptome profiling may allow standardization and cost reduction of its analysis, which will be the next step for transcriptomics to become a canon of contemporary cancer medicine.

Broad phenotypic spectrum of germ line 7p12.1 microdeletions encompassing the IKZF1 gene includes predisposition to acute lymphoblastic leukemia.

Microdeletions of 7p12.1 encompassing the IKZF1 gene locus are rare, with few cases reported. The common phenotype includes intellectual disability, overgrowth, and facial dysmorphism accompanied, albeit rarely, by congenital anomalies. Haploinsufficiency of IKZF1 predisposes individuals to childhood acute lymphoblastic leukemia (ALL). In this study, we comprehensively analyzed the frequency of 7p12.1 deletions among 4581 Polish individuals who underwent chromosomal microarray testing for unexplained developmental delay, intellectual disability, and/or congenital anomalies. Two unrelated individuals (0.04%) with a de novo interstitial 7p12.1 microdeletion encompassing IKZF1 were identified. One developed ALL. Analysis of the incidence and the phenotype of constitutional 7p12.1 microdeletion, which based on the previously annotated patients data in public databases and literature reports, revealed 21 cases including five patients diagnosed with ALL.

The Regulation of Collagen Processing by miRNAs in Disease and Possible Implications for Bone Turnover.

This article describes several recent examples of miRNA governing the regulation of the gene expression involved in bone matrix construction. We present the impact of miRNA on the subsequent steps in the formation of collagen type I. Collagen type I is a main factor of mechanical bone stiffness because it constitutes 90-95% of the organic components of the bone. Therefore, the precise epigenetic regulation of collagen formation may have a significant influence on bone structure. We also describe miRNA involvement in the expression of genes, the protein products of which participate in collagen maturation in various tissues and cancer cells. We show how non-collagenous proteins in the extracellular matrix are epigenetically regulated by miRNA in bone and other tissues. We also delineate collagen mineralisation in bones by factors that depend on miRNA molecules. This review reveals the tissue variability of miRNA regulation at different levels of collagen maturation and mineralisation. The functionality of collagen mRNA regulation by miRNA, as proven in other tissues, has not yet been shown in osteoblasts. Several collagen-regulating miRNAs are co-expressed with collagen in bone. We suggest that collagen mRNA regulation by miRNA could also be potentially important in bone metabolism.

Major Histocompatibility Complex Genes as Therapeutic Opportunity for Immune Cold Molecular Cancer Subtypes.

Current immunotherapies are effective only in a subset of patients, likely due to several factors including defects in tumor cell antigen presentation, decreased response to immune effectors, and molecular heterogeneity of cancers. Recent molecular classifications enable the categorization of many tumor types. However, deregulation of major histocompatibility complex (MHC) gene expression is poorly characterized in the context of molecular cancer subtypes. To suppress the confounding effect of immune infiltrates on expression patterns of immunoregulators, we identified and removed genes with strong correlation to estimated immune compartment levels in each tumor type. Next, we reanalyzed a total of 13 TCGA cancer types encompassing 5651 tumors and 485 normal adjacent tissues by performing unsupervised clustering of 14 MHC genes. Subsequently, resultant clusters were statistically compared in terms of expression of other immune-related genes. Three MHC expression clusters were discovered by unsupervised clustering. We identified concordantly decreased expression of MHC genes (MHC-low) in 26 out of 55 molecular subtypes. Consequently, our study underlines the urgent need for designing strategies to enhance tumor MHC expression that could improve immune cold tumor rejection by cytotoxic T lymphocytes.

Transcriptomic Profiling for the Autophagy Pathway in Colorectal Cancer.

The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted), ATG9B and LAMP1 genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by DRAM1 upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation.

Expression Analysis of Tyrosine Phosphatase Genes at Different Stages of Renal Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. CONCLUSION: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.

Genetic testing in Poland and Ukraine: should comprehensive germline testing of BRCA1 and BRCA2 be recommended for women with breast and ovarian cancer?

PURPOSE: To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations. METHODS: Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1. No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total. RESULTS: We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2, respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2). CONCLUSIONS: These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.

The First Evidence of Cryptosporidium meleagridis Infection in a Colon Adenocarcinoma From an Immunocompetent Patient.

Objectives: The potential linkage between Cryptosporidium spp. infection and colorectal human cancer was suggested by limited reports showing higher prevalence of C. parvum and C. hominis in patients with colon cancer. Here we conducted research concerning presence of Cryptosporidium spp. in malignant tissue collected from patients with colorectal cancer. Methods: Cancerous colon tissue samples collected from 145 non-HIV infected patients with colorectal cancer were screened for Cryptosporidium spp. by immunofluorescence antibody test and genus-specific nested polymerase chain reaction followed by sequencing. Results: Screened pathogen was found in cancerous tissue originating from immunocompetent man with colon adenocarcinoma. Genotyping revealed presence of Cryptosporidium meleagridis. The presence of Cryptosporidium life cycle stages (oocysts and endogenous stages) in colon carcinoma tissue was confirmed by genus-specific FITC-labeling. Conclusions: Herein, we report on a C. meleagridis infection of a colon adenocarcinoma in an immunocompetent patient. This is the first report of C. meleagridis infection in the human colon and first evidence of active development of this species in cancer tissue.

Clinical Observation of a Child with Prenatally Diagnosed De Novo Partial Trisomy of Chromosome 20.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) represent a group of structural chromosome rearrangements that cannot be characterized by conventional cytogenetic analysis, but can be identified by microarray studies. sSMCs are observed in approximately 0.075% of prenatal cytogenetic tests with clinical pathology in no more than 30% of sSMCS carriers. CASE: We present a boy who was diagnosed prenatally with a partial trisomy of chromosome 20. An increased nuchal translucency NT >99%tile, fetal neck cysts and abnormalities of the lumbosacral spine were observed in prenatal screening. After birth, facial dysmorphism, small male genitalia and defects of the vertebrae were observed. In the fourth year of life, dysmorphic features, brachydactyly, small male genitalia, short stature, psychomotor delay, hyperactivity as well as conductive hearing loss became apparent. CONCLUSION: Partial trisomy of chromosome 20, covering the region 20q21→20q23, results in serious clinical complications, including dysmorphic features and delay in psychomotor development.

Meta-analysis of association between Arg326Gln (rs1503185) and Gln276Pro (rs1566734) polymorphisms of PTPRJ gene and cancer risk.

Protein tyrosine phosphatase receptor type J (PTPRJ, DEP1) is a tumour suppressor gene that negatively regulates such processes as angiogenesis, cell proliferation and migration and is one of the genes important for tumour development. Similar to other phosphatase genes, PTPRJ is also described as an oncogene. Among various genetic changes characteristic for this gene, single nucleotide polymorphisms (SNPs) constituting benign genetic variants that can modulate its function have been described. We focused on Gln276Pro and Arg326Gln missense polymorphisms and performed a meta-analysis using data from 2930 and 852 patients for Gln276Pro and Arg326Gln respectively in different cancers. A meta-analysis was performed based on five articles accessed via the PubMed and Research Gate databases. Our meta-analysis revealed that for Arg326Gln, the presence of the Arg (C) allele was associated with lower risk of some cancers, the strongest association was observed for colorectal cancer patients, and there was no association between Gln276Pro (G>T) polymorphism and cancer risk. The polymorphisms Arg326Gln and Gln276Pro of the PTPRJ gene are not associated with an increased risk of cancer except for the Arg326Gln polymorphism in colorectal cancer. Large-scale studies should be performed to verify the impact of this SNP on individual susceptibility to colorectal cancer for given individuals.

Bendamustine alone or with rituximab modifies expression of apoptosis-regulating genes and proteins of CLL cells, depending on IGVH mutational status.

We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies in vitro expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients. BENDA and BENDA + RIT increased expression of BAX and BBC3 in IGVH-MUT and IGVH-UNMUT groups, and significant differences in expression of above genes after BENDA + RIT were observed between both groups. Additionally, BENDA + RIT decreased NFκB and BCL-2 genes in IGVH-UNMUT patients and increased expression of P53, BAX and PUMA proteins in IGVH-MUT and UNMUT subjects. However, no significant differences were found between these groups. In conclusion, BENDA + RIT modified gene expression profile in CLL cells and affected expression of some apoptosis-regulating proteins in vitro. Expression of BAX and BBC3 depends on action of drugs and IGVH mutational status.

[Perinatal palliative care performed in obstetrics and neonatology wards and hospices for children - own experience].

OBJECTIVE: Lethal defects lead to the intrauterine death of the fetus or the passing away of the child immediately after birth or in early infancy, regardless of the treatment used. In the case of lethal defects, it is not possible to effectively help the child, despite using the most modern equipment or medicines in the treatment or the progress made by medicine. Parents, who decide to continue the pregnancy, although the fetus has a lethal defect that cannot be cured, may be covered by perinatal hospice care, which is comprehensive and consists in supporting the pregnant woman during the prenatal time, during delivery and after delivery and support of her family, giving full information to the parents about their child's illness. Childcare after birth is focused on protecting the infant from persistent therapy and providing him with appropriate conditions. Aim: To demonstrate the role of perinatal palliative care for pregnant women in whom the results of prenatal tests pointed to a severe developmental disorder in the fetus with a potentially lethal prognosis, and to present a pattern of behavior for their hospitalization in the perinatal hospice. PATIENTS AND METHODS: Materials and methods: The retrospective analysis included documentation of 67 patients referred to the RAZEM (TOGETHER) Program in Wroclaw in 2014-2018 due to abnormal results of (ultrasound and / or genetic) prenatal tests, which indicated a serious developmental disorder in the fetus with potentially lethal prognosis. Analysis was conducted of sociodemographic data, clinical data on fetal diagnosis, pregnancy and delivery, the procedure for prenatal delivery and postnatal birth. RESULTS: Results: 67 women aged 20-43 years (mean 31.2) were referred to the RAZEM Program. Out of these, 57 women were enrolled for palliative care, which accounted for 85% of those referred to the program. Palliative care was continued in 51 patients, because 6 women decided to terminate their pregnancy during the diagnostic process (10.5%). The most common abnormalities in the fetuses were chromosomal aberrations, CNS defects and kidney defects. In 95% of the cases, intrauterine fetal death or neonatal death occurred. CONCLUSION: Conclusions: Perinatal palliative care is an indispensable form of care for pregnant women in whom the results of prenatal tests indicate a serious developmental disorder in the fetus with potentially lethal prognosis. The in-hospital model of a perinatal hospice is a beneficial form of care, as it ensures consistency and good communication in the team, which favourably affects its quality.

The Influence of Tumor Microenvironment on ATG4D Gene Expression in Colorectal Cancer Patients.

Despite great progress in research on the subject, the involvement of autophagy in colorectal cancer (CRC) pathogenesis (initiation, progression, metastasis) remains obscure and controversial. Autophagy is a catabolic process, fundamental to cell viability and connected with degradation/recycling of proteins and organelles. In this study, we aimed at investigating the relative expression level of mRNA via Real-Time PCR of 16 chosen genes belonging to Atg8 mammalian orthologs and their conjugation system, comprising GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3C, ATG3, ATG7, ATG10, ATG4A, ATG4B, ATG4C, ATG4D, and three genes encoding proteins building the multimeric ATG16L1 complex, namely ATG5, ATG12, and ATG16L1, in 73 colorectal tumors and paired adjacent normal colon mucosa. Our study demonstrated the relative downregulation of all examined genes in CRC tissues in comparison to adjacent noncancerous mucosa, with the highest rate of expression in both tumor and non-tumor tissues observed for GAPARBPL2 and the lowest for MAP1LC3C. Moreover, in patients with advanced-stage tumors and high values of regional lymph nodes, statistically significant downregulation of ATG4D expression in adjacent normal cells was observed. Our study confirms the role of autophagy genes as cancer suppressors in colorectal carcinogenesis. Furthermore, in regard to the ATG4D gene, we observed the influence of tumor microenvironments on gene expression in adjacent colon mucosa.

Multilevel omic data clustering reveals variable contribution of methylator phenotype to integrative cancer subtypes.

AIM: We aimed to assess to what extent CpG island methylator phenotype (CIMP) contributes to cancer subtypes obtained by multilevel omic data analysis. MATERIALS & METHODS: 16 The Cancer Genome Atlas datasets encompassing three data layers in 4688 tumor samples were analyzed. We identified cancer integrative subtypes (ISs) by the use of similarity network fusion and consensus clustering. CIMP high (CIMP-H) associated ISs were profiled by gene sets and transcriptional regulators enrichment analysis. RESULTS & CONCLUSION: In nine out of 16 cancer datasets CIMP-H clusters significantly overlaped with unique ISs. The contribution of CIMP-H on integrative molecular profiling is variable; therefore, only in a subset of cancer types does CIMP-H contribute to homogenous integrative subtype. CIMP-H associated ISs are heterogenous groups with regard to deregulated pathways and transcriptional regulators.

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.