Ciliopathies are a broad range of inherited developmental and degenerative diseases associated with structural or functional defects in motile or primary non-motile cilia. There are around 200 known ciliopathy disease genes and whilst genetic testing can provide an accurate diagnosis, 24–60% of ciliopathy patients who undergo genetic testing do not receive a genetic diagnosis. This is partly because

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect

Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the post-LT fibrogenesis,

Next-generation sequencing (NGS) is an incredibly useful tool for genetic disease diagnosis. However, the most commonly used bioinformatics methods for analyzing sequence reads insufficiently discriminate genomic regions with extensive sequence identity, such as gene families and pseudogenes, complicating diagnostics. This problem has been recognized for specific genes, including many involved in human

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further

Genomic sequencing advances have increased the potential to identify secondary findings (SFs). Current guidelines recommend the analysis of 59 medically actionable genes; however, patient preferences indicate interest in learning a broader group of SFs. We aimed to develop an analytical pipeline for the efficient analysis and return of all clinically significant SFs. We developed a pipeline consisting

Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are

In recent years, large efforts have been made to unravel the role of the gut microbiota in inflammatory bowel disease (IBD), which is a chronic inflammatory disorder of the gastro-intestinal tract. Considering the heterogeneity patients with IBD display in their disease course and response to treatment, there is a big need in translating these findings towards clinical practise. In this perspective

Copy number variation (CNV) related disorders tend to show complex phenotypic profiles that do not match known diseases. This makes it difficult to ascertain their underlying molecular basis. A potential solution is to compare the affected genomic regions for multiple patients that share a pathological phenotype, looking for commonalities. Here, we present a novel approach to associate phenotypes with

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied

Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure

In an effort to characterize the people who composed the groups known as the Xiongnu, nuclear and whole mitochondrial DNA data were generated from the skeletal remains of 52 individuals excavated from the Tamir Ulaan Khoshuu (TUK) cemetery in Central Mongolia. This burial site, attributed to the Xiongnu period, was used from the first century BC to the first century AD. Kinship analyses were conducted

Paired-box (PAX) genes encode a family of highly conserved transcription factors found in vertebrates and invertebrates. PAX proteins are defined by the presence of a paired domain that is evolutionarily conserved across phylogenies. Inclusion of a homeodomain and/or an octapeptide linker subdivides PAX proteins into four groups. Often termed “master regulators”, PAX proteins orchestrate tissue and

Chromosomal insertions are thought to be rare structural rearrangements. The current understanding of the underlying mechanisms of their origin is still limited. In this study, we sequenced 16 cases with apparent simple insertions previously identified by karyotyping and/or chromosomal microarray analysis. Using mate-pair genome sequencing (GS), we identified all 16 insertions and revised previously

The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations

High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted

To explore mutations in the additional sex combs-like 3 (ASXL3) gene in two Chinese families with congenital heart disease (CHD). Whole-exome sequencing (WES) was used to reveal a novel compound heterozygous mutation in the ASXL3 gene that was associated with CHD. Sanger sequencing of a further 122 CHD patients was used to determine an additional compound heterozygous mutation in the ASXL3 gene. Cell

We present selected topics of population genetics and molecular phylogeny. As several excellent review articles have been published and generally focus on European and American scientists, here, we emphasize contributions by Japanese researchers. Our review may also be seen as a belated 50-year celebration of Motoo Kimura’s early seminal paper on the molecular clock, published in 1968.

Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50–80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case–control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbGaP, PanScan I/II, PanC4 and GERA data sets. We then

The genomes of present-day humans outside Africa originated almost entirely from a single out-migration ~ 50,000–70,000 years ago, followed by mixture with Neanderthals contributing ~ 2% to all non-Africans. However, the details of this initial migration remain poorly understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data

Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects.

Whole exome sequencing (WES)-based assays undergo rigorous validation before being implemented in diagnostic laboratories. This validation process generates experimental evidence that allows laboratories to predict the performance of the intended assay. The NA12878 Genome in a Bottle (GIAB) HapMap reference sample is commonly used for validation in diagnostic laboratories. We investigated what data

As the most common cardiac arrhythmia, atrial fibrillation (AF) is a major risk factor for stroke, heart failure, and premature death with considerable associated costs. However, no available treatment options have optimal benefit-harm profiles currently, reflecting an incomplete understanding of the biological mechanisms underlying this complex arrhythmia. Recently, molecular epidemiological studies

CRISPR-Cas9 are widely used for gene targeting in mice and rats. The non-homologous end-joining (NHEJ) repair pathway, which is dominant in zygotes, efficiently induces insertion or deletion (indel) mutations as gene knockouts at targeted sites, whereas gene knock-ins (KIs) via homology-directed repair (HDR) are difficult to generate. In this study, we used a double-stranded DNA (dsDNA) donor template

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over

The homeodomain transcription factors (TFs) Pax6 (OMIM: 607108) and Prox1 (OMIM: 601546) critically regulate gene expression in lens development. While PAX6 mutations in humans can cause cataract, aniridia, microphthalmia, and anophthalmia, among other defects, Prox1 deletion in mice causes severe lens abnormalities, in addition to other organ defects. Furthermore, the optimal dosage/spatiotemporal

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic

The chromosomal region critical in Down syndrome has long been analyzed through genotype–phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5′ UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual

Vascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways including TIE2, PIK3CA and GNAQ/11. Yet, a portion of individuals with clinical features of VA do not have variants in these genes, suggesting that there are undiscovered pathogenic factors underlying these patients and possibly with

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of function of a set of imprinted genes on chromosome 15q11–15q13. One of these genes, NDN, encodes necdin, a protein that is important for neuronal differentiation and survival. Loss of Ndn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20–30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton

In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing

The development of next-generation sequencing technologies has opened-up some new possibilities to explore the contribution of genetic variants to human diseases and in particular that of rare variants. Statistical methods have been developed to test for association with rare variants that require the definition of testing units and, in these testing units, the selection of qualifying variants to include

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless

An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent

Multicellular eukaryotes emerged late in evolution from an ocean of viruses, bacteria, archaea, and unicellular eukaryotes. These macroorganisms are exposed to and infected by a tremendous diversity of microorganisms. Those that are large enough can even be infected by multicellular fungi and parasites. Each interaction is unique, if only because it operates between two unique living organisms, in

Clinically significant copy-number variants (CNVs) known to cause human diseases are routinely detected by chromosomal microarray analysis (CMA). Recently, genome sequencing (GS) has been introduced for CNV analysis; however, sequencing depth (determined by sequencing read-length and read-amount) is a variable parameter across different laboratories. Variating sequencing depths affect the CNV detection

In the original article publication, the affiliation of the author Ana Coutinho is incorrect.

Cone-rod dystrophy (CORD) is an inherited retinal degenerative disease characterized by progressive loss of cone and rod photoreceptors. Although several genes have been reported to cause autosomal dominant CORD (adCORD), the genetic causes of adCORD have not been fully elucidated. Here, we identified the ATP1A3 gene, encoding the α3 subunit of Na+, K+-ATPase, as a novel gene associated with adCORD

Human papillomaviruses (HPVs) infect mucosal or cutaneous stratified epithelia. There are 5 genera and more than 200 types of HPV, each with a specific tropism and virulence. HPV infections are typically asymptomatic or result in benign tumors, which may be disseminated or persistent in rare cases, but a few oncogenic HPVs can cause cancers. This review deals with the human genetic and immunological

We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome

Anti-cytokine autoantibodies may cause immunodeficiency and have been recently recognized as 'autoimmune phenocopies of primary immunodeficiencies' and are found in particular, but not exclusively in adult patients. By blocking the cytokine's biological function, patients with anti-cytokine autoantibodies may present with a similar clinical phenotype as the related inborn genetic disorders. So far

Genome-wide association studies (GWAS) have been successful in identifying and confirming novel genetic variants that are associated with diverse HIV phenotypes. However, these studies have predominantly focused on European cohorts. HLA molecules have been consistently associated with HIV outcomes, some of which have been found to be population specific, underscoring the need for diversity in GWAS

Over the last decade next generation sequencing (NGS) has been extensively used to identify new pathogenic mutations and genes causing rare genetic diseases. The efficient analyses of NGS data is not trivial and requires a technically and biologically rigorous pipeline that addresses data quality control, accurate variant filtration to minimize false positives and false negatives, and prioritization

Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals

During the past decade, genetic studies of schizophrenia have become one of the most exciting and fast-moving areas. Hundreds of genes implicated in schizophrenia have been identified by genetic, epigenetic, and gene expression studies. However, how to systematically and efficiently use these published data to pinpoint the causal genes becomes a major challenge in schizophrenia research. Here, we release

We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic

Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients

In the original article published, the "p" value in the Fig. 5 legend is incorrectly presented as *p < 0.50. The correct p value is *p < 0.050.

Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in

ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and

GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization. Deoxygalactonojirimycin (DGJ) and its derivatives are pharmaceutical chaperones that directly

Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described

We provide a Kazakh whole genome sequence (MJS) and analyses with the largest comparative Kazakh genomic data available to date. We found 102,240 novel SNVs and a high level of heterozygosity. ADMIXTURE analysis confirmed a significant proportion of variations in this individual coming from all continents except Africa and Oceania. A principal component analysis showed neighboring Kalmyk, Uzbek, and