Biology subjects

Lal, D.

Publications and source records attributed to Lal, D..

9 recordsLinked to original sources

bioRxiv2018

The role of sodium channels in sudden unexpected death in pediatrics

Sudden Unexpected Death in Pediatrics (SUDP) is a tragic condition with hypothesized multifactorial etiology. While there is recent evidence implicating genes related to cardiac arrhythmia and epilepsy as genetic risk factors contributing to some cases of SUDP, the underlying mechanisms of SUDP remain under active investigation. SUDP encompasses Sudden Infant Death Syndrome (SIDS) and Sudden Unexplained Death in Childhood (SUDC), affecting children under and over 1 year of age, respectively. The presence of developmental hippocampal malformations in many children with SIDS and SUDC suggests that a subset of patients may share epilepsy-related mechanisms with Sudden Unexplained Death in Epilepsy Patients (SUDEP). Pathogenic variants in both epilepsy- and arrhythmia-related sodium channel genes have recently been identified in patients with SIDS, SUDC, and SUDEP.\n\nWe performed a candidate gene analysis for genes encoding sodium channel subunits in whole exome sequencing (WES) data from 73 SUDP patients. After a thorough literature review, we mapped all reported SUDP-associated sodium channel variants alongside variants from the population on a structural protein model to evaluate whether patient variants clustered in important protein domains compared to controls.\n\nIn our cohort, 13 variants met criteria for pathogenicity or potential pathogenicity. While SCN1A, SCN1B, and SCN5A have established disease associations, we also considered variants in the paralogs SCN3A, SCN4A and SCN9A. Overall, the patient-associated variants clustered at conserved amino acid sites across the sodium channel gene family that do not tolerate variation in these genes.\n\nThis study provides a molecular overview of sodium channel variants present in cases with SUDP and reveals key amino acid sites that do not tolerate variation across the SCN paralog family. Further research will lead to an improved understanding of the contribution of sodium channels to SUDP, with a goal of one day implementing prevention strategies to avoid untimely deaths in at-risk children.\n\nAuthor SummaryThe sudden unexplained death of an infant or a child is a tragic event, which is likely caused by the complex interaction of multiple factors. Besides environmental factors, genes related to epilepsy and cardiac arrhythmia have been identified as risk factors. The sodium channel family encompasses genes, related to both cardiac arrhythmia as well as epilepsy, whose proteins share structural homology. We evaluated sodium channel gene variants in our cohort, examined all known variants in sodium genes in SUDP patients from the literature, and mapped patient variants alongside variants from the population on a 3D protein model. The patient variants clustered at conserved amino acid sites with low rates of variation in the general population, not only in the particular gene involved but also in the gene family. This study illustrates that sodium channel variants contribute to the complex phenotype of sudden death in pediatrics, suggesting complex mechanisms of neurologic and/or cardiac dysfunction contributing to death.

genetics↗

bioRxiv2018

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

The contribution of de novo and ultra-rare genetic variants in severe and moderate intellectual disability (ID) has been extensively studied whereas the genetic architecture of mild ID has been less well characterized. To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals.\n\nWe show that rare damaging variants in genes known to be associated with cognitive defects are observed more often in severe (27%) than in mild ID (13%) patients (p-value: 7.0e-4). We further observed a significant enrichment of protein truncating variants in loss-of-function intolerant genes, as well as damaging missense variants in genes not yet associated with cognitive defects (OR: 2.1, p-value: 3e-8). For the first time to our knowledge, we show that a common variant polygenic load significantly contributes to all severity forms of ID. The heritability explained was the highest for educational attainment (EDU) in mild ID explaining 2.2% of the heritability on liability scale. For more severe ID it was lower at 0.6%. Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria. The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection.

genetics↗

bioRxiv2017

Common variant burden contributes significantly to the familial aggregation of migraine in 1,589 families

It has long been observed that complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. Two competing hypotheses exist, emphasizing either rare or common genetic variation. More specifically, familial aggregation could be predominantly explained by rare, penetrant variants that segregate according to Mendelian inheritance or rather by the sufficient polygenic accumulation of many common variants, each with an individually small effect. Some combination of both common and rare variation could also contribute towards a spectrum of disease risk.\n\nWe investigated this in a collection of 8,319 individuals across 1,589 migraine families from Finland. Family members were individually diagnosed by a migraine-specific questionnaire with either migraine without aura (MO, ICHD-3 code 1.1, n=2,357), migraine with typical aura (ICHD- 3 code 1.2.1, n=2,420), hemiplegic migraine (HM, ICHD-3 code 1.2.3, n=540), or no migraine (n=3,002). For comparison, we used population-based migraine cases (n=1,101) and controls (n=13,369) from the FINRISK study. The disease status of FINRISK individuals was assigned based on health registry data from outpatient clinics and/or prescription medication. All individuals were genotyped on the Illumina(R) CoreExome or PsychArray chip platforms and imputed to a Finnish reference panel of 6,962 haplotypes. Polygenic risk scores (PRS), representing the common variant burden in each individual, were calculated using weights from the most recent large-scale genome-wide association study of migraine. To account for family structure in our analyses, we used a mixed-model approach, adjusting for the genetic relationship matrix as a random effect.\n\nWe found a significantly higher common variant burden in familial cases of migraine (for all subtypes, measured by the odds ratio [OR] per standard deviation [SD] increase in PRS; OR = 1.76, 95% CI = 1.71-1.81, P = 1.7x10-109) compared to cases from a population cohort (OR = 1.32, 95% CI = 1.25-1.38, P = 7.2x10-17) when using the population controls as a reference group. The highest enrichment was observed for HM (OR = 1.96, 95% CI = 1.86-2.07, P = 8.7x10-36) and migraine with typical aura (OR = 1.85, 95% CI = 1.79-1.91, P = 1.4x10-86) but enrichment was also present for MO (OR = 1.57, 95% CI = 1.51-1.63, P = 1.1x10-48). Comparing within cases, there was no significant difference in common variant burden between the migraine with aura subtypes, HM and migraine with typical aura (OR = 1.09, 95% CI = 0.99-1.19, P = 0.09), but both showed significantly higher enrichment compared to MO (OR = 1.28, 95% CI = 1.17-1.38, P = 7.3x10-7, and OR = 1.17, 95% CI = 1.11-1.23, P = 4.62x10-5, respectively). Additionally, we found that higher common variant burden corresponded to earlier age of headache onset (OR per SD increase in PRS for 3,631 cases with onset before 20 years old compared to 1,686 cases with onset later than 20 years old; OR = 1.11, 95% CI = 1.05-1.18, P = 8.3x10-4). FINRISK population cases identified from national health registry data were found to have lower common variant burden in comparison to the familial migraine cases (OR = 1.32, 95% CI = 1.25-1.38, P = 6.8x10-17), unless the individuals had attended both a specialist clinic and also received prophylactic migraine treatment (OR = 1.70, 95% CI = 1.53-1.88, P = 3.9x10-9). Finally, although rare variants have been suggested as the primary cause for familial hemiplegic migraine (FHM), we found only four out of 45 sequenced FHM families (8.9%) with a pathogenic mutation in one of the known risk genes.\n\nIn summary, our results demonstrate a substantial contribution of common polygenic variation to familial aggregation in migraine, comparable to both controls and that observed in migraine cases from a population cohort. The findings also suggest that individuals with migraine aura symptoms (either typical aura, which is mostly visual, or rare motor aura) tend to have higher common variant burden on average supporting the polygenic model also in these migraine subtypes.

genetics↗

bioRxiv2017

Paternal-age-related de novo mutations and risk for five disorders

BackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.\n\nMethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.\n\nResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01-1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).\n\nConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

genetics↗

bioRxiv2017

Gene family information facilitates variant interpretation and identification of disease-associated genes

Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paralogs and belong to gene families. It has not been thoroughly investigated how gene family information can be utilized for disease gene discovery and variant interpretation. We developed a paralog conservation score to empirically evaluate whether paralog conserved or nonconserved sites of in-human paralogs are important for protein function. Using this score, we demonstrate that disease-associated missense variants are significantly enriched at paralog conserved sites across all disease groups and disease inheritance models tested. Next, we assessed whether gene family information could assist in discovering novel disease-associated genes. We subsequently developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in more than 10k neurodevelopmental disorder patients. 33 gene family enriched genes represent novel candidate genes which are brain expressed and variant constrained in neurodevelopmental disorders.

genetics↗

bioRxiv2017

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

BackgroundMicrodeletions are known to confer risk to epilepsy, particularly at genomic rearrangement \"hotspot\" loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.\n\nMethodsWe assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.\n\nResultsWhen hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00x10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22x10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78x10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.\n\nConclusionsOur results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.

genetics↗

bioRxiv2017

Duplications at 19q13.33 in patients with neurodevelopmental disorders

OBJECTIVEAfter recent publication of the first patients with disease associated missense variants in GRIN2D, we evaluate the effect of copy number variation (CNV) overlapping this gene towards the presentation of neurodevelopmental disorders.\n\nMETHODSWe explored ClinVar (N{degrees}CNV = 41,398) and DECIPHER (N{degrees}CNV = 30,222) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content and expression with publicly available reference databases.\n\nRESULTSWe identified 13 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo and comparable CNVs are not present in control databases. All patients were reported to have neurodevelopmental disorders and dysmorphic features as the most common clinical phenotype (N= 10/13), followed by seizures (N= 6/13) and intellectual disability (N= 5/13). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression and gene dosage sensitivity analysis, we highlight four genes for future evaluation: CARD8, C19orf68, KDELR1 and GRIN2D, which are promising candidates for disease causality. Further, investigation of the literature especially supports GRIN2D as the best candidate gene.\n\nCONCLUSIONSOur study presents dup19q13.33 as novel duplication syndrome locus associated with neurodevelopmental disorders. CARD8, C19orf68, KDELR1 and GRIN2D are promising candidates for functional follow up.

genetics↗

bioRxiv2017

Reassessment Of Lesion-Associated Gene And Variant Pathogenicity In Focal Human Epilepsies

PurposeIncreasing availability of surgically resected brain tissue from Focal Cortical Dysplasia and low-grade epilepsy-associated tumor patients fostered large-scale genetic examination. However, assessment of germline and somatic variant pathogenicity remains difficult.\n\nMethodsHere, we critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 12 disease-related genes and 88 neuropathology-associated missense variants. We (1) assessed evolutionary gene constraint using the pLI and missense z scores, (2) applied guidelines by the American College of Medical Genetics and Genomics (ACMG), and (3) predicted pathogenicity by using PolyPhen-2, CADD, and GERP.\n\nResultsConstraint analysis classified only seven out of 12 genes to be likely disease-associated, while 35 (40%) of those 88 variants were classified as being variants of unknown significance (VUS) and 53 (60%) as being likely pathogenic (LPII). Pathogenicity prediction yielded discrimination between neuropathology-associated variants (LPII and VUS) and rare variant scores obtained from individuals present in the Genome Aggregation Database (gnomAD).\n\nConclusionWe conclude that several VUS are likely disease-associated and will be reclassified by future molecular evidence. In summary, interpretation of lesion-associated gene variants remains complex while the application of current ACMG guidelines including bioinformatic pathogenicity prediction will help improving interpretation and prediction.

genetics↗

bioRxiv2017

The Spectrum Of De Novo Variants In Neurodevelopmental Disorders With Epilepsy

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

genetics↗