There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.Main abbreviationsPTV= Protein Truncating VariantsPI= Protein Truncating IntolerantPI-PTV= Protein Truncating Variant in genes that are Intolerant to Protein Truncating Variants

Rare% loss)of)function% variants% in% KMT2F% are% associated% with%schizophrenia%and%developmental%disorders%

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz‐like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome‐wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy‐number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next‐generation sequencing. Overall, the DubS‐like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

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Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic diseases characterized by impaired hematopoiesis and progression to acute myeloid leukemia (AML). Although rare, several monogenic causes of familial MDS/AML have recently been molecularly defined. We studied two families with variable manifestation of cytopenia, MDS with cytogenetic aberrations involving chromosome 7, immunodeficiency, and neurologic disease consistent with ataxia-pancytopenia syndrome. Genetic studies uncovered heterozygous missense variants (p.Arg986Cys and p.Ile891Thr) in SAMD9L, a tumor suppressor gene located on chromosome 7. Consistent with a gain-of-function effect, transfection and over-expression of both SAMD9L variants decreased cell proliferation relative to wild-type protein. In the two families, a total of 10 individuals heterozygous for either SAMD9L mutation were identified. Three individuals developed MDS, with monosomy 7 or der(1;7)(q10;p10) as cytogenetic aberrations that encompassed the mutant SAMD9L locus. In an additional five individuals, three of which experienced a spontaneously resolved cytopenic episodes in infancy, we detected mosaic copy-neutral loss of heterozygosity of 7q by uniparental disomy, with loss of the mutated allele, or mosaic cis SAMD9L mutations. By digital PCR, we identified these events in hematopoietic progenitor cell populations, which were further enriched in B and NK cell lineages. Absent in non hematological tissues, these mutations thus represented somatic revertant mosaicism. Clinically, revertant mosaicism was associated with reduced disease severity, although in two individuals neurological manifestations persisted. Of note, two unaffected carriers without revertant mosaicism harbored an additional rare in trans germline SAMD9L p.Thr233Asn missense variant. In cellular assays, the SAMD9L p.Thr233Asn variant increased proliferation, indicating a loss-of-function effect that potentially compensates for the SAMD9L p.Arg986Cys mutation. Together, our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause a disease with cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with chromosome 7 aberrations, where hematopoietic revertant mosaicism is common and ameliorates the clinical presentation. Disclosures Fioretos: Cantargia: Equity Ownership.