Familial posterior predominant subcortical band heterotopia caused by a CEP85L missense mutation

Lissencephaly comprises a spectrum of cortical malformations caused by disruption of neuronal migration. The lissencephaly spectrum includes agyria defined as cortex lacking gyri with sulci >3cm apart, pachygyria defined as abnormally broad gyri with sulci 1.5-3cm apart, and subcortical band heterotopia (SBH) characterised by a band of heterotopic neurons beneath the cortex, separated by a thin layer of white matter. Lissencephaly has heterogeneous genetic aetiologies, including both single gene mutations (for example, LIS1 and DCX variants) and locus deletions (for example, 17p13.3 deletion causing Miller-Dieker syndrome). A systematic analysis of a large lissencephaly cohort, found a causative mutation in 81% of children, with pathogenic variants in LIS1, DCX, TUBA1A and DYNC1H1 accounting for 69% of all cases. Mutations in specific lissencephaly genes correlated with particular patterns of brain MRI abnormalities: DCX mutations were associated with anterior predominant lissencephaly and LIS1 mutations with posterior predominant lissencephaly. Most unsolved cases had posterior predominant lissencephaly. Heterozygous variants in the CEP85L gene were first identified as a cause of lissencephaly in 2020. Here we highlight the characteristic clinico-radiological CEP85L phenotype in an Irish family with parieto-occipital SBH and focal epilepsy.</p

KBG syndrome mimicking genetic generalized epilepsy

•Several conditions may mimic Genetic Generalized Epilepsy GGE. •GGE is less frequently misdiagnosed compared to other subtypes of epilepsy. •KBG syndrome is a rare autosomal dominant condition. •KBG syndrome may mimic GGE.</p

A novel monoallelic <i>ALG5 </i>variant causing late-onset ADPKD and tubulointerstitial fibrosis

Introduction Monoallelic variants in the ALG5 gene encoding asparagine-linked glycosylation protein 5 homolog (ALG5) have been recently shown to disrupt polycystin-1 (PC1) maturation and trafficking via underglycosylation, causing an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype and interstitial fibrosis. In this report, we present clinical, genetic, histopathologic, and protein structure and functional correlates of a new ALG5 variant, p.R79W, that we identified in 2 distant genetically related Irish families displaying an atypical late-onset ADPKD phenotype combined with tubulointerstitial damage. Methods Whole exome and targeted sequencing were used for segregation analysis of available relatives. This was followed by immunohistochemistry examinations of kidney biopsies, and targeted (UMOD, MUC1) and untargeted plasma proteome and N-glycomic studies. Results We identified a monoallelic ALG5 variant [GRCh37 (NM_013338.5): g.37569565G>A, c.235C>T; p.R79W] that cosegregates in 23 individuals, of whom 18 were clinically affected. We detected abnormal localization of ALG5 in the Golgi apparatus of renal tubular cells in patients’ kidney specimens. Further, we detected the pathological accumulation of uromodulin, an N-glycosylated glycosylphosphatidylinositol (GPI)-anchored protein, in the endoplasmic reticulum (ER), but not mucin-1, an O- and N-glycosylated protein. Biochemical investigation revealed decreased plasma and urinary uromodulin levels in clinically affected individuals. Proteomic and glycoproteomic profiling revealed the dysregulation of chronic kidney disease (CKD)-associated proteins. Conclusion ALG5 dysfunction adversely affects maturation and trafficking of N-glycosylated and GPI anchored protein uromodulin, leading to structural and functional changes in the kidney. Our findings confirm ALG5 as a cause of late-onset ADPKD and provide additional insight into the molecular mechanisms of ADPKD-ALG5.</p

Whole exome sequencing studies in epilepsy: a deep analysis of the published literature

To evaluate the quality of whole-exome sequencing (WES) reporting in the epilepsy literature. We aimed to assess the quality of reporting of WES in epilepsy. We compared studies based on journal type and if outcome reporting biases exist. We used a self-constructed benchmark to quantitatively analyze studies. We included 451 publications. Reporting was heterogeneous with poor reporting of (1) ACMG guideline application 13% and (2) Human Phenotype Ontology (HPO) numbers in 3% of studies, 3) VUS in 19%. Predictors of reporting included journal type and journal impact factor. Date of publication and publication type were not predictors of poor reporting. Pairwise comparisons of genetics versus neurology journals using relative risks yielded significant differences in reporting of ACMG guideline application (RR 1.88, 95% CI 1.04-3.38); HPO numbers (RR 8.62, 95% CI 1.08-63.37) and deposition of findings to ClinVar (RR 2.50, 95% CI 1.03-6.1). Reporting of WES literature is heterogeneous in quality, and poor reporting hinders collaboration and accession of data into large databases like OMIM and OrphaNet. This study highlights reporting bias in this area and, formal structural guidelines like the CONSORT guidelines used in the reporting of clinical trials are needed to address the issue

Germline mosaicism in a family with MBD5 haploinsufficiency

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene causes a neurodevelopmental disorder that includes intellectual disability, developmental delay, speech impairment, seizures, sleep disturbances, and behavioral difficulties. Microdeletion of 2q23.1 is the most common cause of haploinsufficiency, although MBD5 haploinsufficiency may also cause this genetic disorder. We report a family harboring a heterozygous loss-of-function variant in MBD5 (NM_018328.5:c.728delC; p.Pro243Hisfs*26), which includes three affected siblings with varying phenotypic features. Both parents were phenotypically normal but deep coverage sequencing of the parents showed germline mosaicism in the mother. </p

Everolimus precision therapy for the GATOR1-related epilepsies: a case series

Background: Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. Methods: We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. Results: Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3%-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. Conclusions: Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.</p

Diagnostic utility of genetic testing in patients undergoing renal biopsy

High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease

Familial variability of disease severity in adult patients with ADPKD

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Methods To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity. Results Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = Conclusion Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.</p

Familial variability of disease severity in adult patients with ADPKD

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Methods To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity. Results Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = Conclusion Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.</p

Development of a genomics module within an epilepsy-specific electronic health record: Toward genomic medicine in epilepsy care

Objectives: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease.Methods: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system.Results: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management.Significance: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.</div