• Known pathogenic germ line variants in 12 genes can explain nearly 30% of families with inherited predisposition to MDS/AML. • Asymptomatic carriers of germ line RUNX1 mutations develop detectable clonal hematopoiesis with a cumulative risk of .80% by age 50 years.Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families. (Blood. 2015;126(22):2484-2490

Deletions involving chromosome 1p are frequent events in multiple myeloma (MM). As karyotyping and single nucleotide polymorphism-based mapping analysis identify a minimal common deletion region involving the 1p21 locus, we investigated the prevalence and prognostic significance of del(1p21) in 203 MM patients undergoing high-dose therapy and autologous SCT. 1p21 status was also evaluated in 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 41 patients with plasma cell leukemia (PCL). FISH combined with cytoplasmic light chain detection (cIg-FISH) detected hemizygous 1p21 deletions in 18% of the MM, 34% of PCL but none of the MGUS cases. The presence of 1p21 deletions was correlated with 1q21(CKS1B) amplification (P ¼ 0.01), and del17p(TP53) (P ¼ 0.05) but not with del(13q), t(11;14) or t(4;14). Patients with 1p21 deletions had significantly shorter progression-free survival (PFS; median 14.2 vs 25.4 months, Po0.001) and overall survival (OS; median 39.4 vs 82.3 months, P ¼ 0.001) than those without such deletions. In multivariate analysis, del(1p21) was an independent risk factor for PFS (P ¼ 0.003) and OS (P ¼ 0.013) after adjusting for del(13q), del(p53), t(4;14) and 1q21 amplifications. Our results indicate that del(1p21) is an independent poor prognostic factor associated with disease progression in MM. IntroductionChromosome 1 abnormalities are among the most common cytogenetic findings in multiple myeloma (MM), constituting the structural aberrations in up to 40% of abnormal karyotypes. 1 They are associated with adverse outcome. 2 The short arm of chromosome 1 is preferentially involved in deletions and the long arm in gains. 3,4 Recently, Marzin et al. 5 reported that 27% of 36 MM cases had 1p deletions identified by karyotype analysis, and the smallest common deletion region was 1p12-1p21. Using single nucleotide polymorphism-based mapping, Walker et al. 4 found that 7 (23%) of 30 MM cases had 1p deletions, confirming a minimal common deletion region between band 1p12 and 1p21.1. In a pilot study, we evaluated the clinical relevance of 1p21 deletions by cytoplasmic Ig interphase FISH (cIg-FISH) in a cohort of 87 MM patients, and found that 1p21 deletion confers a poor clinical outcome. 6 To further explore its prognostic significance and potential implication in the genetic risk stratification of MM, we expanded our previous observation to a larger MM cohort and examined 1p21 deletions in the context of myeloma-associated genetic risk factors including t(4;14), del(13q), del(17p) and 1q21 (CKS1B) amplifications. In addition, we compared 1p21 status in different stages of plasma cell dyscrasia. Fluorescence in situ hybridization On institutional ethics board approval, BM aspirates were obtained from patients with active MM before any treatment. Mononuclear cells enriched by Ficoll-gradient centrifugation and cytospin slides were made and stored at À70 1C. Cytoplasmic Ig light chain immunofluorescence with simultaneous FISH analysis (cIg-FISH) was performed on fixed mononucl...

BackgroundRecent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, we examined the extent to which two neurodevelopmental traits that are non-specific to ASD—inattention/hyperactivity and motor coordination—might contribute to ASD recurrence in siblings of ASD probands.MethodsData from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire.ResultsAmong siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R 2 = 0.53) and quantitative ASD trait burden (R 2 = 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings.ConclusionsThese findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment—axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed—jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific (“BASINS”) may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9212-y) contains supplementary material, which is available to authorized users.

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Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes. Patients had a median of two (range 1-7) previous therapies in this cohort. A total of 119 out of 143 (83%) patients had an objective response, with median time to progression (TTP) and overall survival (OS) of 11 and 28 months, respectively. Patients with del(1p21) or del(17p) (p53) deletions had a significantly shorter TTP. OS was shorter in patients with 1p21 or 17p deletions, but did not reach statistical significance. Prior bortezomib or thalidomide treatment was associated with shorter TTP and OS. Multivariate analysis identified del(17p), del(1p21), and prior bortezomib or thalidomide therapy as independent risk factors for shorter TTP. Our data suggest that chromosome 17p and 1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated patients with relapsed/refractory MM. Improved therapeutic strategies are required for these patients.