研究者詳細 - アレクシッチ　ブランコ

Case reports of two siblings with autism spectrum disorder and 15q13.3 deletions

Furukawa, S; Kushima, I; Aleksic, B; Ozaki, N

NEUROPSYCHOPHARMACOLOGY REPORTS 43 巻 ( 3 ) 頁： 462 - 466 2023年9月

記述言語：英語出版者・発行元：Neuropsychopharmacology Reports

Background: Copy number variations (CNVs) have been implicated in psychiatric and neurodevelopmental disorders. Especially, 15q13.3 deletions are strongly associated with autism spectrum disorder (ASD), intellectual disability (ID), schizophrenia (SCZ), attention deficithyperactivity disorder (ADHD), and mood disorder. Case Presentation: We present two siblings with ASD. They had a father with bipolar disorder (BD). Patient 1 is a 21-year-old female with ASD and mild ID, who had language delay and repetitive behavior in childhood, social difficulties, and refused to go to school because of bullying. She was hospitalized in a psychiatric hospital several times. Patient 2 is a 19-year-old male with ASD and ADHD. He did not have developmental delay, but had social difficulties and impulsiveness, then refused to go to school because of bullying. He was treated by a psychiatrist for anxiety and disrupted sleep rhythms. Array comparative genomic hybridization was performed for the siblings and parents. 15q13.3 deletions were detected in the siblings and their healthy mothers. No other pathogenic CNVs were detected. We performed whole-genome sequencing of the family and identified 13 rare missense variants in brain-expressed genes, which may be responsible for the phenotypic differences between the siblings and their mother. Conclusions: This study shows incomplete penetrance and variable expressivity in 15q13.3 deletions. We detected second-hit variants that may explain the phenotypic differences within this family. In addition, detecting 15q13.3 deletions may lead to early diagnosis and a better prognosis with careful follow-up.

DOI： 10.1002/npr2.12340

Slovenian Version of the Drug-Induced Extrapyramidal Symptoms Scale Evaluation of Interrater and Test-Retest Reliability

Senica, N; Aleksic, B; Inada, T; Iljes, AP; Zamuda, T; Kumperscak, HG

JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 43 巻 ( 4 ) 頁： 361 - 364 2023年7月

記述言語：英語出版者・発行元：Journal of Clinical Psychopharmacology

Aim The Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) is a multidimensional rating scale for the assessment of drug-induced extrapyramidal symptoms (EPS), developed in 1994. It is suitable for evaluating EPS considering the degree of influence EPS has on daily activities and the subjective distress that it causes. Method This study to evaluate the interrater and test-retest reliability of the DIEPSS Slovenian version conducted at the University Medical Center Maribor in Slovenia in November 2018. Results Six raters performed the interrater assessment of 135 DIEPSS video clips with recordings of patients with EPS. A second assessment was then performed by 2 raters to evaluate the test-retest reliability, which was high (interclass correlation coefficients from 0.743 to 0.936). Conclusions The results for the Slovenian language version of the DIEPSS show high interrater and test-retest reliability, with high concordance rates for all evaluated items (interclass correlation coefficient > 0.8).

DOI： 10.1097/JCP.0000000000001682

De novo<i> MCM6</i> variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

Smits, DJ; Schot, R; Popescu, CA; Dias, KR; Ades, L; Briere, LC; Sweetser, DA; Kushima, I; Aleksic, B; Khan, S; Karageorgou, V; Ordonez, N; Sleutels, FJGT; van der Kaay, DCM; Van Mol, C; Van Esch, H; Bertoli-Avella, AM; Roscioli, T; Mancini, GMS

HUMAN GENETICS 142 巻 ( 7 ) 頁： 949 - 964 2023年7月

記述言語：英語出版者・発行元：Human Genetics

The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

DOI： 10.1007/s00439-023-02569-7

Family correspondence with his parents and his last companion (years 1780-1798)

The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

Rots D, Jakub TE, Keung C, Jackson A, Banka S, Pfundt R, de Vries BBA, van Jaarsveld RH, Hopman SMJ, van Binsbergen E, Valenzuela I, Hempel M, Bierhals T, Kortüm F, Lecoquierre F, Goldenberg A, Hertz JM, Andersen CB, Kibæk M, Prijoles EJ, Stevenson RE, Everman DB, Patterson WG, Meng L, Gijavanekar C, De Dios K, Lakhani S, Levy T, Wagner M, Wieczorek D, Benke PJ, Lopez Garcia MS, Perrier R, Sousa SB, Almeida PM, Simões MJ, Isidor B, Deb W, Schmanski AA, Abdul-Rahman O, Philippe C, Bruel AL, Faivre L, Vitobello A, Thauvin C, Smits JJ, Garavelli L, Caraffi SG, Peluso F, Davis-Keppen L, Platt D, Royer E, Leeuwen L, Sinnema M, Stegmann APA, Stumpel CTRM, Tiller GE, Bosch DGM, Potgieter ST, Joss S, Splitt M, Holden S, Prapa M, Foulds N, Douzgou S, Puura K, Waltes R, Chiocchetti AG, Freitag CM, Satterstrom FK, De Rubeis S, Buxbaum J, Gelb BD, Branko A, Kushima I, Howe J, Scherer SW, Arado A, Baldo C, Patat O, Bénédicte D, Lopergolo D, Santorelli FM, Haack TB, Dufke A, Bertrand M, Falb RJ, Rieß A, Krieg P, Spranger S, Bedeschi MF, Iascone M, Josephi-Taylor S, Roscioli T, Buckley MF, Liebelt J, Dagli AI, Aten E, Hurst ACE, Hicks A, Suri M, Aliu E, Naik S, Sidlow R, Coursimault J, Nicolas G, Küpper H, Petit F, Ibrahim V, Top D, Di Cara F, Genomics England Research Consortium, Louie RJ, Stolerman E, Brunner HG, Vissers LELM, Kramer JM, Kleefstra T

American journal of human genetics 110 巻 ( 6 ) 頁： 963 - 978 2023年6月

Aleksic, B

EUROPE-REVUE LITTERAIRE MENSUELLE ( 1122 ) 頁： 350 - 351 2022年11月

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Fu J.M., Satterstrom F.K., Peng M., Brand H., Collins R.L., Dong S., Wamsley B., Klei L., Wang L., Hao S.P., Stevens C.R., Cusick C., Babadi M., Banks E., Collins B., Dodge S., Gabriel S.B., Gauthier L., Lee S.K., Liang L., Ljungdahl A., Mahjani B., Sloofman L., Smirnov A.N., Barbosa M., Betancur C., Brusco A., Chung B.H.Y., Cook E.H., Cuccaro M.L., Domenici E., Ferrero G.B., Gargus J.J., Herman G.E., Hertz-Picciotto I., Maciel P., Manoach D.S., Passos-Bueno M.R., Persico A.M., Renieri A., Sutcliffe J.S., Tassone F., Trabetti E., Campos G., Cardaropoli S., Carli D., Chan M.C.Y., Fallerini C., Giorgio E., Girardi A.C., Hansen-Kiss E., Lee S.L., Lintas C., Ludena Y., Nguyen R., Pavinato L., Pericak-Vance M., Pessah I.N., Schmidt R.J., Smith M., Costa C.I.S., Trajkova S., Wang J.Y.T., Yu M.H.C., Aleksic B., Artomov M., Benetti E., Biscaldi-Schafer M., Børglum A.D., Carracedo A., Chiocchetti A.G., Coon H., Doan R.N., Fernández-Prieto M., Freitag C.M., Gerges S., Guter S., Hougaard D.M., Hultman C.M., Jacob S., Kaartinen M., Kolevzon A., Kushima I., Lehtimäki T., Rizzo C.L., Maltman N., Manara M., Meiri G., Menashe I., Miller J., Minshew N., Mosconi M., Ozaki N., Palotie A., Parellada M., Puura K., Reichenberg A., Sandin S., Scherer S.W., Schlitt S.

Nature Genetics 54 巻 ( 9 ) 頁： 1320 - 1331 2022年9月

出版者・発行元：Nature Genetics

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

DOI： 10.1038/s41588-022-01104-0