%0 Journal Article %J Stroke %D 2020 %T Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage. %A Biffi, Alessandro %A Urday, Sebastian %A Kubiszewski, Patryk %A Gilkerson, Lee %A Sekar, Padmini %A Rodriguez-Torres, Axana %A Bettin, Margaret %A Charidimou, Andreas %A Pasi, Marco %A Kourkoulis, Christina %A Schwab, Kristin %A DiPucchio, Zora %A Behymer, Tyler %A Osborne, Jennifer %A Morgan, Misty %A Moomaw, Charles J %A James, Michael L %A Greenberg, Steven M %A Viswanathan, Anand %A Gurol, M Edip %A Worrall, Bradford B %A Testai, Fernando D %A McCauley, Jacob L %A Falcone, Guido J %A Langefeld, Carl D %A Anderson, Christopher D %A Kamel, Hooman %A Woo, Daniel %A Sheth, Kevin N %A Rosand, Jonathan %K Aged %K Anticoagulants %K Apolipoprotein E4 %K Cerebral Hemorrhage %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Recurrence %X

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the () gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and genotype predict ICH recurrence. We then developed and validated a combined -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

RESULTS: Cortical superficial siderosis, cerebral microbleed, and ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all <0.05). Combining genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

CONCLUSIONS: Combining MRI and genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

%B Stroke %V 51 %P 2153-2160 %8 2020 07 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/32517581?dopt=Abstract %R 10.1161/STROKEAHA.120.028310 %0 Journal Article %J Genome Res %D 2020 %T Complex mosaic structural variations in human fetal brains. %A Sekar, Shobana %A Tomasini, Livia %A Proukakis, Christos %A Bae, Taejeong %A Manlove, Logan %A Jang, Yeongjun %A Scuderi, Soraya %A Zhou, Bo %A Kalyva, Maria %A Amiri, Anahita %A Mariani, Jessica %A Sedlazeck, Fritz J %A Urban, Alexander E %A Vaccarino, Flora M %A Abyzov, Alexej %X

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200-400 mosaic SNVs per cell in three human fetal brains (15-21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to ∼14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in ∼10% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (∼6200 vs. ∼4000 bp), implying that they may have similar functional consequences.

%B Genome Res %V 30 %P 1695-1704 %8 2020 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33122304?dopt=Abstract %R 10.1101/gr.262667.120 %0 Journal Article %J Genet Med %D 2019 %T Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. %A Guo, Hui %A Duyzend, Michael H %A Coe, Bradley P %A Baker, Carl %A Hoekzema, Kendra %A Gerdts, Jennifer %A Turner, Tychele N %A Zody, Michael C %A Beighley, Jennifer S %A Murali, Shwetha C %A Nelson, Bradley J %A Bamshad, Michael J %A Nickerson, Deborah A %A Bernier, Raphael A %A Eichler, Evan E %X

PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD).

METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons.

RESULTS: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family.

CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.

%B Genet Med %V 21 %P 1611-1620 %8 2019 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/30504930?dopt=Abstract %R 10.1038/s41436-018-0380-2 %0 Journal Article %J Acta Neuropathol %D 2019 %T MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. %A Donkervoort, S %A Sabouny, R %A Yun, P %A Gauquelin, L %A Chao, K R %A Hu, Y %A Al Khatib, I %A Töpf, A %A Mohassel, P %A Cummings, B B %A Kaur, R %A Saade, D %A Moore, S A %A Waddell, L B %A Farrar, M A %A Goodrich, J K %A Uapinyoying, P %A Chan, S H S %A Javed, A %A Leach, M E %A Karachunski, P %A Dalton, J %A Medne, L %A Harper, A %A Thompson, C %A Thiffault, I %A Specht, S %A Lamont, R E %A Saunders, C %A Racher, H %A Bernier, F P %A Mowat, D %A Witting, N %A Vissing, J %A Hanson, R %A Coffman, K A %A Hainlen, M %A Parboosingh, J S %A Carnevale, A %A Yoon, G %A Schnur, R E %A Boycott, K M %A Mah, J K %A Straub, V %A Foley, A Reghan %A Innes, A M %A Bönnemann, C G %A Shutt, T E %X

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

%B Acta Neuropathol %8 2019 Aug 29 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/31463572?dopt=Abstract %R 10.1007/s00401-019-02059-z