Hara, Kaori



School of Medicine, Department of Pediatrics (Shinanomachi)



Career 【 Display / hide

  • 2015.04

    慶應義塾大学医学部小児科学教室, 助教

Academic Background 【 Display / hide

  • 2002.04

    Keio Univercity, medicine

    University, Graduated

  • 2018.04

    Keio University, 医学部, 医学研究科博士課程

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Coursework, 2022.03

Licenses and Qualifications 【 Display / hide

  • 小児科専門医, 2013.10

  • 周産期(新生児)専門医, 2016.12


Research Areas 【 Display / hide

  • Life Science / Genetics (ゲノムインプリンティング)

  • Life Science / Embryonic medicine and pediatrics

Research Keywords 【 Display / hide

  • インプリンティング異常症

  • ビタミンD

  • 新生児学


Papers 【 Display / hide

  • Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

    Hara-Isono K., Matsubara K., Nakamura A., Sano S., Inoue T., Kawashima S., Fuke T., Yamazawa K., Fukami M., Ogata T., Kagami M.

    Clinical Epigenetics (Clinical Epigenetics)  15 ( 1 )  2023.12

    ISSN  18687075

     View Summary

    Background: Our previous study suggested that assisted reproductive technology (ART) may be a possible risk factor for the development of epimutation-mediated imprinting disorders (epi-IDs) for mothers aged ≥ 30 years. However, whether ART or advanced parental age facilitates the development of uniparental disomy-mediated IDs (UPD-IDs) has not yet been investigated. Results: We enrolled 130 patients with aneuploid UPD-IDs including various IDs confirmed by molecular studies and obtained ART data of the general population and patients with epi-IDs from a robust nationwide database and our previous report, respectively. We compared the proportion of ART-conceived livebirths and maternal childbearing age between patients with UPD-IDs and the general population or patients with epi-IDs. The proportion of ART-conceived livebirths in patients with aneuploid UPD-IDs was consistent with that in the general population of maternal age ≥ 30 years and was lower than that in the patients with epi-IDs, although there was no significant difference. The maternal childbearing age of patients with aneuploid UPD-IDs was skewed to the increased ages with several cases exceeding the 97.5th percentile of maternal childbearing age of the general population and significantly higher than that of patients with epi-IDs (P < 0.001). In addition, we compared the proportion of ART-conceived livebirths and parental age at childbirth between patients with UPD-IDs caused by aneuploid oocytes (oUPD-IDs) and that by aneuploid sperm (sUPD-IDs). Almost all ART-conceived livebirths were identified in patients with oUPD-IDs, and both maternal age and paternal age at childbirth were significantly higher in patients with oUPD-IDs than in patients with sUPD-IDs. Because maternal age and paternal age were strongly correlated (rs = 0.637, P < 0.001), higher paternal age in oUPD-IDs was explained by the higher maternal age in this group. Conclusions: Different from the case of epi-IDs, ART itself is not likely to facilitate the development of aneuploid UPD-IDs. We demonstrated that advanced maternal age can be a risk factor for the development of aneuploid UPD-IDs, particularly oUPD-IDs.

  • Seasonal variation in vitamin D status of Japanese infants starts to emerge at 2 months of age: a retrospective cohort study

    Takahashi K., Arimitsu T., Hara-Isono K., Ikeda K.

    British Journal of Nutrition (British Journal of Nutrition)  129 ( 11 ) 1908 - 1915 2023.06

    ISSN  00071145

     View Summary

    Vitamin D seasonality has been reported in adults and children, suggesting that sunlight exposure has effects on 25(OH)D production. While vitamin D deficiency among infants has received significant attention, little is known about the extent to which vitamin D status during early infancy is affected by sunlight exposure. Here, we retrospectively analysed serum 25(OH)D levels of 692 samples obtained from healthy infants aged 1-2 months born at Saitama City Hospital, Japan (latitude 35·9° North) between August 2017 and September 2021. Data regarding the frequency of outdoor activities, formula intake and BMI were also collected and analysed. Month-to-month comparisons of vitamin D levels revealed significant variation in 25(OH)D levels in breastfed infants starting at 2 months, with maximal and minimal levels in September and January, respectively. An outdoor activity score of 0 was most common at 1 month (83·9 %) and a score of 3 was most common at 2 months (81·2 %), suggesting an increased amount of sunlight exposure at 2 months. Multiple linear regression analysis revealed the amount of formula intake to be significantly associated with vitamin D status at both 1 (t = 17·96) and 2 months (t = 16·30). Our results comprise the first evidence that seasonal variation of vitamin D begins at 2 months among breastfed infants from East Asia, though dietary intake appears to be the major determinant of vitamin D status. These findings provide new insights into the influence of dietary and non-dietary factors on vitamin D status during early infancy.

  • Frequency and clinical characteristics of distinct etiologies in patients with Silver-Russell syndrome diagnosed based on the Netchine-Harbison clinical scoring system

    Fuke T., Nakamura A., Inoue T., Kawashima S., Hara-Isono K., Matsubara K., Sano S., Yamazawa K., Fukami M., Ogata T., Kagami M.

    Journal of Human Genetics (Journal of Human Genetics)  67 ( 10 ) 607 - 611 2022.10

    ISSN  14345161

     View Summary

    Silver-Russel syndrome (SRS) is a representative imprinting disorder (ID) characterized by growth failure and diagnosed by clinical features. Recently, international consensus has recommended using the Netchine-Harbison clinical scoring system (NH-CSS) as clinical diagnostic criteria. Loss of methylation of H19/IGF2:intergenic differentially methylated region (H19LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) are common etiologies of SRS; however, other IDs, pathogenic variants (PVs) of genes, and pathogenic copy number variants (PCNVs) have been reported in patients meeting NH-CSS. To clarify the frequency and clinical characteristics of each etiology, we conducted (epi)genetic analysis in 173 patients satisfying NH-CSS. H19LOM and UPD(7)mat were identified in 34.1%. PCNVs, other IDs, and PVs were in 15.0%. Patients with all six NH-CSS items were most frequently observed with H19LOM and UPD(7)mat. This study confirmed the suitability of NH-CSS as clinical diagnostic criteria, the (epi)genetic heterogeneity of SRS, and showed the necessity of further discussion regarding the “SRS spectrum”.

  • Pathogenic Copy Number and Sequence Variants in Children Born SGA With Short Stature Without Imprinting Disorders

    Hara-Isono K., Nakamura A., Fuke T., Inoue T., Kawashima S., Matsubara K., Sano S., Yamazawa K., Fukami M., Ogata T., Kagami M.

    Journal of Clinical Endocrinology and Metabolism (Journal of Clinical Endocrinology and Metabolism)  107 ( 8 ) E3121 - E3133 2022.08

    ISSN  0021972X

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    Context: Children born small-for-gestational-age with short stature (SGA-SS) is associated with (epi)genetic defects, including imprinting disorders (IDs), pathogenic copy number variants (PCNVs), and pathogenic variants of genes involved in growth. However, comprehensive studies evaluating these 3 factors are very limited. Objective: To clarify the contribution of PCNVs and candidate pathogenic variants to SGA-SS. Design: Comprehensive molecular analyses consisting of methylation analysis, copy number analysis, and multigene sequencing. Methods: We enrolled 140 patients referred to us for genetic testing for SGA-SS. Among them, we excluded 42 patients meeting Netchine- Harbison clinical scoring system criteria for Silver-Russell syndrome and 4 patients with abnormal methylation levels of the IDs-related differentially methylated regions. Consequently, we conducted copy number analysis and multigene sequencing for 86 SGA-SS patients with sufficient sample volume. We also evaluated clinical phenotypes of patients with PCNVs or candidate pathogenic variants. Results: We identified 8 (9.3%) and 11 (12.8%) patients with PCNVs and candidate pathogenic variants, respectively. According to the American College of Medical Genetics standards and guidelines, 5 variants were classified as pathogenic and the remaining 6 variants were classified as variants of unknown significance. Genetic diagnosis was made in 12 patients. All patients with PCNVs or candidate pathogenic variants did not correspond perfectly to characteristic clinical features of each specific genetic cause. Conclusion: We clarified the contribution of PCNVs and pathogenic variants to SGA-SS without IDs. Comprehensive molecular analyses, including copy number analysis and multigene sequencing, should be considered for patients with unknown SGA-SS etiology.

  • CDKN1C hyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inherited KCNQ1OT1:TSS-DMR

    Hara-Isono K., Yamazawa K., Tanaka S., Nishi E., Fukami M., Kagami M.

    Journal of Medical Genetics (Journal of Medical Genetics)  59 ( 12 ) 1241 - 1246 2022.07

    ISSN  00222593

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    Background Two imprinting control centres, H19/IGF2:IG-differentialy methylated region (DMR) and KCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited. Cases Patient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS. Molecular analyses Both patients showed hypermethylation of the KCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls. Conclusion Paternal deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.

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