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Genetic testing of patient constitutional DNA (i.e., their genome) is increasingly performed in medical practice. Sequencing an entire human genome (about 3.2 billion nucleotides) is now possible to complete in days to weeks, and at a similar cost to some advanced imaging tests or to a brief admission to hospital. Genome sequencing is being integrated into health care systems internationally, most notably in the UK. Starting in 2021, genome sequencing is being performed as a clinical genetic test in Ontario, Canada. Genome sequencing is broader in scope than other commonly used genetic tests, and data can be analyzed in both hypothesis-driven and hypothesis-generating ways. For these reasons, genome sequencing will likely eventually supplant exome sequencing, large next-generation sequencing gene panel tests and chromosomal microarray analysis. Genome sequencing is a consideration for children and adults with suspected genetic disorders for whom a targeted genetic testing approach is unlikely to succeed or has already failed.

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants. Polygenic risk scores are nearing a level of differentiation required for their clinical utility in risk prediction in populations with high-risk rare pathogenic genetic variants.

Background RAC3 encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants in RAC3 can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.MethodsWe investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) in RAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.ResultsIn vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.ConclusionOur results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.

Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. We showed that rare TREs in schizophrenia may impact synaptic functions by disrupting the splicing process of their associated genes in a loss-of-function manner. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.

Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N 6 -methyladenosine (m 6 A) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of m 6 A target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose m 6 A sites on target EPRS1 mRNA, or by m 6 A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA m 6 A sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders. Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.

Purpose: Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined. Methods: We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions. Results: We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4–BP5) region, including seven novel adult cases from local cohorts. No BP4–BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin ( P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases. Conclusion: The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care. Genet Med 17 2, 149–157.

Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.

Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that are also associated with rare Mendelian disorders. The use of cancer mutation data to aid in the interpretation of germline missense variants, regardless of whether the gene is associated with a hereditary cancer predisposition syndrome or a non-cancer-related developmental disorder, has not been systematically assessed. We extracted putative cancer driver missense mutations from the Cancer Hotspots database and annotated them as germline variants, including presence/absence and classification in ClinVar. We trained two supervised learning models (logistic regression and random forest) to predict variant classifications of germline missense variants in ClinVar using Cancer Hotspot data (training dataset). The performance of each model was evaluated with an independent test dataset generated in part from searching public and private genome-wide sequencing datasets from ~1.5 million individuals. Of the 2,447 cancer mutations, 691 corresponding germline variants had been previously classified in ClinVar: 426 (61.6%) as likely pathogenic/pathogenic, 261 (37.8%) as uncertain significance, and 4 (0.6%) as likely benign/benign. The odds ratio for a likely pathogenic/pathogenic classification in ClinVar was 28.3 (95% confidence interval: 24.2–33.1, p < 0.001), compared with all other germline missense variants in the same 216 genes. Both supervised learning models showed high correlation with pathogenicity assessments in the training dataset. There was high area under precision-recall curve values (0.847 and 0.829) and area under the receiver-operating characteristic curve values (0.821 and 0.774) for logistic regression and random forest models, respectively, when applied to the test dataset. With the use of cancer and germline datasets and supervised learning techniques, our study shows that cancer mutation data can be leveraged to improve the interpretation of germline missense variation potentially causing rare Mendelian disorders.

Objective To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage‐gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. Methods We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole‐cell voltage clamp electrophysiological recording of wild‐type versus variants in a heterologous mammalian expression system. Results We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Interpretation Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3‐expressing high frequency‐ firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical‐genetic syndrome within the spectrum of KCNC1‐related neurological disorders.