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De novo structural variants are an important cause of rare disorders but remain poorly understood. Here, the authors analyse over 12,000 families and reveal the prevalence, diversity, and clinical impact of complex de novo structural variants.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Analysis of rare de novo mutations in gene regulatory elements suggests that 1–3% of patients with neurodevelopmental disorders carry such mutations in elements that are active in the fetal brain.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

Matthew Hurles and colleagues report the sequencing of breakpoints for over 300 CNVs detected in genomes of three individuals, using targeted hybridization-based DNA capture and 454-sequencing.

Matthew Hurles, David FitzPatrick and colleagues report the discovery of four novel Mendelian disorders based on their analysis of exome sequence data from 4,125 families with diverse rare developmental disorders. They present their analytical pipeline as a general strategy for the discovery of genetic causes of autosomal recessive disorders.

Matthew Hurles and colleagues sequence the genomes of three multi-sibling families and investigate the rates and spectra of germline mutation. Their analyses suggest that the mutation rate per cell division is higher during early embryogenesis than in post-pubertal spermatogenesis.

A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

Matthew Hurles and colleagues report the first direct comparative analysis of male and female germline mutation rates from whole-genome sequences of two parent-offspring trios sequenced as part of the 1000 Genomes Project. They identify variation in paternal and maternal mutation rates between these two families.

Caroline Wright, Matthew Hurles and Helen Firth propose that a principle of proportionality be applied to genomic data that weighs the depth of data (what is shared) against the breadth of sharing (with whom) to find a proportionate approach that balances beneficence and non-maleficence.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Andrew Jackson, Grant Stewart, Bernd Wollnik and colleagues identify TRAIP mutations in three patients with primordial dwarfism. They show that TRAIP is involved in DNA damage response during genome replication and is necessary for efficient cell cycle progression.

Matt Hurles and colleagues present a general statistical framework for copy number variation (CNV) association tests in a case-control study design. They show that existing strategies for CNV association with binary disease phenotypes are complicated by differential errors and poor clustering quality. Here they report new methods, robust to these factors, which apply likelihood ratio testing to constrained Gaussian mixture models of quantitative CNV signals in cases and controls. Their methods are assay and platform independent, and implemented in freely available CNVtools software.

Human genetic variants that impair genes that are intolerant of damaging genetic variation are associated with lower reproductive success that is probably mediated by genetically associated cognitive and behavioural traits, particularly in males.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

A study of 21,879 families with rare genetic diseases identifies 12 with 2- to 7-fold excess of germline mutations, most of which are due to DNA repair defects or exposure to mutagenic chemotherapy, although most individuals with a hypermutated genome will not have a genetic disease.

Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Patients with neurodevelopmental conditions without a monogenic diagnosis have a higher polygenic burden than those with a monogenic diagnosis. Non-transmitted common alleles in the parents are associated with the child’s phenotype, and the common and rare variants conferring risk are correlated.

How the epigenomic landscape linked to transcription regulates human embryonic development is unclear. Here, the authors analyse the dynamics of H3K27Ac, H3K4me3 and H3K27me3 during the period when organs first assemble as a platform for understanding noncoding developmental disorders.

Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.

Bernd Wollnik and colleagues report mutations in CEP152 cause Seckel syndrome, which is characterized by short stature, severe microcephaly and mental retardation. The work suggests that CEP152 has a function in genome maintenance.

The contribution of copy number variation to obesity — a highly heritable and genetically heterogeneous disorder — is investigated in 300 Caucasian patients to reveal that large, rare deletions are significantly enriched in patients compared to controls. Several rare copy number variants are identified that are recurrent in patients but absent or at much lower prevalence in controls.

Andrew Jackson, Peter Nürnberg and colleagues identify mutations in PLK4 and TUBGCP6 in individuals with microcephaly, primordial dwarfism, retinopathy and other congenital anomalies. These findings extend the spectrum of human phenotypes associated with centriole dysfunction.

The DeNovoGear software detects de novo point mutations and indels with high specificity in familial and somatic tissue sequence data.

Copy number variants (CNVs) account for a major proportion of human genetic diversity and may contribute to genetic susceptibility to disease. Here, a large, genome-wide study of association between common CNVs and eight common human diseases is presented. The study provides a wealth of technical insights that will inform future study design and analysis. The results also indicate that common CNVs that can be 'typed' on existing platforms are unlikely to contribute much to the genetic basis of common diseases.

Saturation genome editing characterizes BAP1 variants and their association with disease presentation. A phenome-wide association analysis in the UK finds that BAP1 variants identified as deleterious in the study are associated with higher serum IGF-1 levels.

Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.

Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.