Small Pedigrees Research Articles

Variant ranking pipeline for complex familial disorders

Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.

Functional characterization of SORL1 variants in cell-based assays to investigate variant pathogenicity.

SORLA, the protein encoded by the SORL1 gene, has an important role in recycling cargo proteins to the cell surface. While SORLA loss-of-function variants occur almost exclusively in Alzheimer's disease cases, the majority of SORL1 variants are missense variants that are individually rare and can have individual mechanisms how they impair SORLA function as well as have individual effect size on disease risk. However, since carriers mostly come from small pedigrees, it is challenging to determine variant penetrance, leaving clinical significance associated with most missense variants unclear. In this article, we present functional approaches to evaluate the pathogenicity of a SORL1 variant, p.D1105H. First, we generated our mutant receptor by inserting the D1105H variant into the full-length SORLA-WT receptor. Then using western blot analysis we quantified the effect of the mutation on maturation and shedding of the receptor for transfected cells, and finally applied a flow cytometry approach to quantify SORLA expression at the cell surface. The results showed decreased maturation, decreased shedding, and decreased cell surface expression of D1105H compared with wild-type SORLA. We propose how these approaches can be used to functionally assess the pathogenicity of SORL1 variants in the future. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.

Problems of collecting genetic history, interpretation of pedigrees with common and rare dermatological, skeletal, dental and other peculiarities that affect the appearance and health of a human

The aim of the study was to analyze the problem of constructing and interpreting human pedigrees, which include some signs that are easily detected during a clinical examination and the collection of primary history. Materials and methods. 2 pedigrees from own sources and 2 pedigrees of famous people from literary sources are presented. They serve as the examples of using the provided data for further medical and genealogical analysis. Results and discussion. The results indicate that pedigree analysis is a primary and informationally important tool for the further algorithm of diagnosis and treatment of subjects. The effect of the quantity, quality and testing level of the presented genealogical information for a full pedigree analysis and the use of its possibilities is demonstrated.Pedigree analysis demonstrated that the number of absolute units of quantitative information presented (total number of generations and members of the pedigree) and absolute units of qualitative information (traits/medical conditions listed and their level of detail) may not be associated with the value of genetic conclusions. It has been shown that the largest number of members in a generation is usually represented for the generation of the propositus.Thus, smaller pedigrees, where more units of information are represented per member, can be of greater value for genetic conclusions. An analysis of one's own pedigrees showed that, on average, less than one trait can be represented per person in the pedigree. Additionally, small pedigrees with available molecular genetic data may be of greatest value, even retrospectively. Conclusions. It is shown that pedigrees can represent valuable primary information for clinicians regarding the further algorithm of the subject dealing and serve as a tool for the scientific thinking development in the educational process

Approaching autozygosity in a small pedigree of Gochu Asturcelta pigs

BackgroundIn spite of the availability of single nucleotide polymorphism (SNP) array data, differentiation between observed homozygosity and that caused by mating between relatives (autozygosity) introduces major difficulties. Homozygosity estimators show large variation due to different causes, namely, Mendelian sampling, population structure, and differences among chromosomes. Therefore, the ascertainment of how inbreeding is reflected in the genome is still an issue. The aim of this research was to study the usefulness of genomic information for the assessment of genetic diversity in the highly endangered Gochu Asturcelta pig breed. Pedigree depth varied from 0 (founders) to 4 equivalent discrete generations (t). Four homozygosity parameters (runs of homozygosity, FROH; heterozygosity-rich regions, FHRR; Li and Horvitz’s, FLH; and Yang and colleague’s FYAN) were computed for each individual, adjusted for the variability in the base population (BP; six individuals) and further jackknifed over autosomes. Individual increases in homozygosity (depending on t) and increases in pairwise homozygosity (i.e., increase in the parents’ mean) were computed for each individual in the pedigree, and effective population size (Ne) was computed for five subpopulations (cohorts). Genealogical parameters (individual inbreeding, individual increase in inbreeding, and Ne) were used for comparisons.ResultsThe mean F was 0.120 ± 0.074 and the mean BP-adjusted homozygosity ranged from 0.099 ± 0.081 (FLH) to 0.152 ± 0.075 (FYAN). After jackknifing, the mean values were slightly lower. The increase in pairwise homozygosity tended to be twofold higher than the corresponding individual increase in homozygosity values. When compared with genealogical estimates, estimates of Ne obtained using FYAN tended to have low root-mean-squared errors. However, Ne estimates based on increases in pairwise homozygosity using both FROH and FHRR estimates of genomic inbreeding had lower root-mean-squared errors.ConclusionsParameters characterizing homozygosity may not accurately depict losses of variability in small populations in which breeding policy prohibits matings between close relatives. After BP adjustment, the performance of FROH and FHRR was highly consistent. Assuming that an increase in homozygosity depends only on pedigree depth can lead to underestimating it in populations with shallow pedigrees. An increase in pairwise homozygosity computed from either FROH or FHRR is a promising approach for characterizing autozygosity.

The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.

Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.

A Novel Gene CDC27 Causes SLE and Is Associated With the Disease Activity.

BackgroundAs genetic genetic factors are important in SLE, so screening causative genes is of great significance for the prediction and early prevention in people who may develop SLE. At present, it is very difficult to screen causative genes through pedigrees. The analytical method described herein can be used to screen causative genes for SLE and other complex diseases through pedigrees.MethodsFor the first time, 24 lupus pedigrees were analyzed by combining whole exon sequencing and a variety of biological information tools including common-specific analysis, pVAAST (pedigree variant annotation, analysis and search tool), Exomiser (Combining phenotype and PPI associated analysis), and FARVAT (family based gene burden), and the causative genes of these families with lupus identified. Selected causative genes in peripheral-blood mononuclear cells (PBMCs) were evaluated by quantitative polymerase chain reaction (qPCR).ResultsCell division cycle 27 (CDC27) was screened out by common-specific analysis and Exomiser causative gene screening. FARVAT analysis on these families detected only CDC27 at the extremely significant level (false discovery rate <0.05) by three family-based burden analyses (BURDEN, CALPHA, and SKATO). QPCR was performed to detect for CDC27 in the PBMCs of the SLE family patients, sporadic lupus patients, and healthy people. Compared with the healthy control group, CDC27 expression was low in lupus patients (familial and sporadic patients) (P<0.05) and correlated with lupus activity indicators: negatively with C-reactive protein (CRP) (P<0.05) and erythrocyte sedimentation rate (P<0.05) and positively with complement C3 and C4 (P<0.05). The CDC27 expression was upregulated in PBMCs from SLE patients with reduced lupus activity after immunotherapy (P<0.05). Based on Receiver operating characteristic (ROC) curve analysis, the sensitivity and specificity of CDC27 in diagnosing SLE were 82.30% and 94.40%.ConclusionThe CDC27 gene, as found through WES combined with multiple analytical method may be a causative gene of lupus. CDC27 may serve as a marker for the diagnosis of SLE and is closely related to the lupus activity. We hope that the analytical method in this study will be used to screen causative genes for other diseases through small pedigrees, especially among non-close relatives.

Bonsai: An efficient method for inferring large human pedigrees from genotype data

SummaryPedigree inference from genotype data is a challenging problem, particularly when pedigrees are sparsely sampled and individuals may be distantly related to their closest genotyped relatives. We present a method that infers small pedigrees of close relatives and then assembles them into larger pedigrees. To assemble large pedigrees, we introduce several formulas and tools including a likelihood for the degree separating two small pedigrees, a generalization of the fast DRUID point estimate of the degree separating two pedigrees, a method for detecting individuals who share background identity-by-descent (IBD) that does not reflect recent common ancestry, and a method for identifying the ancestral branches through which distant relatives are connected. Our method also takes several approaches that help to improve the accuracy and efficiency of pedigree inference. In particular, we incorporate age information directly into the likelihood rather than using ages only for consistency checks and we employ a heuristic branch-and-bound-like approach to more efficiently explore the space of possible pedigrees. Together, these approaches make it possible to construct large pedigrees that are challenging or intractable for current inference methods.

Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning

Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation-phenotype association. At this time, CE has evaluated putative mutation-phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in Mus musculus The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.

A Case of Concurrent Molybdenosis, Secondary Copper, Cobalt and Selenium Deficiency in a Small Sheep Herd in Northern Germany.

Simple SummaryMineral deficiencies are very widespread among small ruminant herds throughout the world and play a big role in small ruminant herd health management. This paper describes the occurrence of a primary molybdenosis causing secondary copper deficiency, combined with ovine white liver disease (cobalt deficiency) and white muscle disease (selenium deficiency) in a group of pastured ram lambs in Northern Germany. To the authors’ knowledge, this is the first proven report of multiple trace element deficiencies in sheep in Germany for decades.To the author’s knowledge this paper describes the first proven report of a combined primary molybdenosis, secondary copper (Cu) deficiency, Ovine White Liver Disease—Cobalt (Co) deficiency, and selenium (Se) deficiency in a small pedigree herd of White Horned Heath sheep in Germany (8 ewes, 2 rams, 3 yearling ewes, 17 lambs) for decades. Clinical signs associated with these mineral deficiencies in a group of pastured ram lambs included emaciation, conjunctivitis, anaemia, growth retardation, discolouration of the wool and photodermatitis. Morbidities and mortalities arose in 4–6-month-old lambs despite intensive veterinary treatment in the summer of 2014 and 2015 (n = 13, 23% died). Se (3/5), Cu (4/7), and Co (3/3) deficiencies in combination with elevated values for Molybdenum (Mo, 2/2) were found. Hamburg is a large industrial city and an input of heavy metals from surrounding industries and coal-fired power stations in combination with a sandy, non-fertilised soil and monoculture grass species might offer a potential explanation for the severity of mineral deficiencies observed in this herd.

Visna in a UK flock and the biosecurity risk arising from the onward sale of likely infected pedigree stock

AbstractSmall ruminant lentivirus infections in sheep most commonly present with respiratory signs (maedi) and indurative mastitis, while primary neurological signs (visna) have rarely been reported in Great Britain (GB). Most reports of visna describe signs referable to myelitis, although central signs associated with encephalitis may feature. In this case, visna was diagnosed in a 4‐year‐old ewe in a small pedigree sheep flock, recently imported to GB from northern Europe. Initial clinical findings were of a head tilt, circling, facial tremors and a unilaterally reduced menace response. These neurological signs progressed to include hyperaesthesia, ipsilateral hemiparesis and recumbency. Flock level infection had recently been diagnosed by serology, and the diagnosis in this individual case was confirmed by serology and histopathology. The subsequent sale of animals from the flock through a large national auction and at private sales raises significant ethical questions and serves as a reminder of the importance of biosecurity precautions.

Comparative proteomics analysis for identifying the lipid metabolism related pathways in patients with Klippel-Feil syndrome.

BackgroundKlippel-Feil syndrome (KFS) represents the rare and complex deformity characterized by congenital defects in the formation or segmentation of the cervical vertebrae. There is a wide gap in understanding the detailed mechanisms of KFS because of its rarity, heterogeneity, small pedigrees, and the broad spectrum of anomalies.MethodsWe recruited eight patients of Chinese Han ethnicity with KFS, five patients with congenital scoliosis (CS) who presented with congenital fusion of the thoracic or lumbar spine and without known syndrome or cervical deformity, and seven healthy controls. Proteomic analysis by data-independent acquisition (DIA) was performed to identify the differential proteome among the three matched groups and the data were analyzed by bioinformatics tools including Gene Ontology (GO) categories and Ingenuity Pathway Analysis (IPA) database, to explore differentially abundant proteins (DAPs) and canonical pathways involved in the pathogenesis of KFS.ResultsA total of 49 DAPs were detected between KFS patients and the controls, and moreover, 192 DAPs were identified between patients with KFS and patients with CS. Fifteen DAPs that were common in both comparisons were considered as candidate biomarkers for KFS, including membrane primary amine oxidase, noelin, galectin-3-binding protein, cadherin-5, glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin-1, CD109 antigen, and eight immunoglobulins. Furthermore, the same significant canonical pathways of LXR/RXR activation and FXR/RXR activation were observed in both comparisons. Seven of DAPs were apolipoproteins related to these pathways that are involved in lipid metabolism.ConclusionsThis study provides the first proteomic profile for understanding the pathogenesis and identifying predictive biomarkers of KFS. We detected 15 DAPs that were common in both comparisons as candidate predictive biomarkers of KFS. The lipid metabolism-related canonical pathways of LXR/RXR and FXR/RXR activation together with seven differentially abundant apolipoproteins may play significant roles in the etiology of KFS and provide possible pathogenesis correlation between KFS and CS.

37 Sibs: an R toolkit for computation of relatedness measures using large pedigrees

Abstract Without appropriate relationships present in a given population, identifying dominance effects in the expression of desirable traits is challenging. Including non-additive effects is desirable to increase accuracy of breeding values. There is no current user-friendly tool package to investigate genetic relatedness in large pedigrees. The objective was to develop and implement efficient algorithms in R to calculate and visualize measures of relatedness (e.g., sibling and family structure, numerator relationship matrices) for large pedigrees. Comparisons to current R packages (Table 1) are also made. Functions to assign animals to families, summary of sibling counts, calculation of numerator relationship matrix (NRM), and NRM summary by groups were created, providing a comprehensive toolkit (Sibs package) not found in other packages. Pedigrees of various sizes (n = 20, 4,035, 120,000 and 132,833) were used to test functionality and compare to current packages. All runs were conducted on a Windows-based computer with an 8 GB RAM, 2.5 GHz Intel Core i7 processor. Other packages had no significant difference in runtime when constructing the NRM for small pedigrees (n = 20) compared to Sibs (0 to 0.05 s difference). However, packages such as ggroups, AGHmatrix, and pedigree were 10 to 15 min slower than Sibs for a 4,035-individual pedigree. Packages nadiv and pedigreemm competed with Sibs (0.30 to 60 s slower than Sibs), but no package besides Sibs was able to complete the 132,833-individual pedigree due to memory allocation issues in R. The nadiv package was closest with a pedigree of 120,000 individuals, but took 37 min to complete (13 min slower than Sibs). This package also provides easier input of pedigrees and is more encompassing of such relatedness measures than other packages (Table 1). Furthermore, it can provide an option to utilize other packages such as GCA for connectedness calculations when using large pedigrees.

A novel mutation in PDE6B in Spanish Water Dogs with early-onset progressive retinal atrophy.

To identify the underlying mutation in a recently identified early-onset progressive retinal atrophy (PRA) in the Spanish Water Dog (SWD) breed. Eighteen SWDs were used in this study. Six SWDs diagnosed with PRA and 12 phenotypically normal SWDs. An exclusion analysis using an established microsatellite panel to screen PRA candidate genes was combined with whole genome sequencing of two affected SWD siblings and two phenotypically normal SWDs (a sibling and the dam). A 6-bp deletion was identified in exon 19 of PDE6B removing two highly conserved amino acids from the enzymatic domain of the PDE6B protein (c.2218-2223del; p.Phe740_Phe741del). This segregated with the disease status in the small study pedigree. Identification of this novel PDE6B mutation adds to the already described PDE6B mutations responsible for PRA in the Irish Setter, Sloughi, and American Staffordshire Terrier dog breeds. A DNA-based test was designed to allow breeders to genotype their animals and make informed breeding decisions in the effort to eradicate PRA from the SWD breed.

Genetic variants in SUSD2 are associated with the risk of ischemic heart disease

Genetic factors partly determine the risk for premature myocardial infarction (MI). We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain-containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N=105,408) for association with IHD. A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87-0.97) in AG heterozygotes and 0.86 (0.62-1.19) in GG homozygotes vs noncarrriers (P-trend=.002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90-0.96) (P=4.6×10-7). The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.

Effects of inbreeding, sex and geographical region on survival in an American bison (Bison bison) population under a captive breeding program

Survival is one of the most important traits to consider for limited animal populations under conservation programs. Here, we estimate the effects of inbreeding, geographical region (Europe, North America and other) and sex on survival at six points of life in American bison populations kept in zoological gardens. The data set consisted of 3893 animals, 1812 males and 2081 females, born between the years 1874 and 2013. We analyzed survival in terms of longevity and survival of the first day after birth. We applied regression analysis with a logistic model. Longevity was examined in terms of six time categories whereas the survival of the first day after birth as a binary trait. We find that the average longevity for the studied population was 5.21 years with a standard deviation of 6.75. The longevity was significantly affected by the sex: females survived on average longer than males. The median values of longevity were considerably lower than the averages and also conditioned by the sex. The largest number of individuals was recorded in survival up to the age of sexual maturity, equal to 43.6% of males and 30.75% of females. More females survived after reaching the age of sexual maturity. Survival of the first day after birth was not influenced by the calf’s sex. There was also detected that the survival of individuals decreased with an increasing level of inbreeding, under relative small pedigree parameters for the population studied. It was also demonstrated that geographical region has a significant effect on the longevity of captive bison.

Investigation of Maternal Effects, Maternal-Fetal Interactions, and Parent-of-Origin Effects (Imprinting) for Candidate Genes Positioned on Chromosome 18q21, in Probands with Schizophrenia and their First-Degree Relatives.

ObjectiveA popular design for the investigation of such effects, including effects of parent-of-origin (imprinting), maternal genotype, and maternal-fetal genotype interactions, is to collect deoxyribonucleic acid (DNA) from affected offspring and their mothers and to compare with an appropriate control sample. We investigate the effects of estimation of maternal, imprinting and interaction effects using multimodal modeling using parents and their offspring with schizophrenia in Korean population. MethodsWe have recruited 27 probands (with schizophrenia) with their parents and siblings whenever possible. We analyzed 20 SNPs of 7 neuronal genes in chromosome 18. We used EMIM analysis program for the estimation of maternal, imprinting and interaction effects using multimodal modeling. ResultsOf analyzed 20 single nucleotide polymorphisms (SNPs), significant SNP (rs 2276186) was suggested in EMIM analysis for child genetics effects (p=0.0225438044) and child genetic effects allowing for maternal genetic effects (p=0.0209453210) with very stringent multiple comparison Bonferroni correction. ConclusionOur results are the pilot study for epigenetic study in mental disorder and help to understanding and use of EMIM statistical genetics analysis program with many limitations including small pedigree numbers.

Hybrid peeling for fast and accurate calling, phasing, and imputation with sequence data of any coverage in pedigrees

BackgroundIn this paper, we extend multi-locus iterative peeling to provide a computationally efficient method for calling, phasing, and imputing sequence data of any coverage in small or large pedigrees. Our method, called hybrid peeling, uses multi-locus iterative peeling to estimate shared chromosome segments between parents and their offspring at a subset of loci, and then uses single-locus iterative peeling to aggregate genomic information across multiple generations at the remaining loci.ResultsUsing a synthetic dataset, we first analysed the performance of hybrid peeling for calling and phasing genotypes in disconnected families, which contained only a focal individual and its parents and grandparents. Second, we analysed the performance of hybrid peeling for calling and phasing genotypes in the context of a full general pedigree. Third, we analysed the performance of hybrid peeling for imputing whole-genome sequence data to non-sequenced individuals in the population. We found that hybrid peeling substantially increased the number of called and phased genotypes by leveraging sequence information on related individuals. The calling rate and accuracy increased when the full pedigree was used compared to a reduced pedigree of just parents and grandparents. Finally, hybrid peeling imputed accurately whole-genome sequence to non-sequenced individuals.ConclusionsWe believe that this algorithm will enable the generation of low cost and high accuracy whole-genome sequence data in many pedigreed populations. We make this algorithm available as a standalone program called AlphaPeel.

Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.

Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain‐of‐function mutations that alter the biophysical properties of the channel. Complete loss‐of‐function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron‐derived cells demonstrated greatly reduced Nav1.6 channel activity without altered gating properties. Hypomorphic alleles of Scn8a in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures.

Analysis of Gene Mutation Related with Hereditary Spherocytosis in a Rhmod Patient of Chinese Han

Objective: Hereditary Spherocytosis (HS) is a cause of hereditary hemolytic anemia with mutations of one or more genes involved in the erythrocyte membrane. An Rhmod patient with mild anemia and spherical red blood cells was found in a small pedigree. His clinical symptoms were similar with that of hereditary spherocytosis. With the purpose of exploring whether the cause of mild anemia was caused by hereditary spherocytosis, HS-related genes, ANK1, SLC4A1, EPB42 were sequenced. Methods: Several exons of ANK1, SLC4A1 and EPB42 were amplified by polymerase chain reactions (PCR) and screened by direct Sanger sequencing. Results: a novel mutation of SLC4A1 (c.1552A>C) was detected. No mutations were found in ANK1 and EPB42 genes. Conclusion: The novel mutations of SLC4A1 might be related to HS. As the patient’s symptoms are similar with hereditary spherocytosis. Consequently, we speculate that anemia in the Rhmod patient may be related to HS.