Publications by authors named "Koji Muroya"

87 Publications

Quantification of serum thyroid hormones using tandem mass spectrometry in patients with Down syndrome.

Biomed Chromatogr 2022 Jan 19;36(1):e5249. Epub 2021 Oct 19.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Thyroid dysfunction is common in patients with Down syndrome (DS), the most common chromosomal disorder. Thyroid hormones (THs) are important for normal growth, neurodevelopment, and metabolism, highlighting the importance of quantifying the levels in patients with DS. However, current methods possess cross-reactivity that results in inaccuracies in quantification. We aimed at developing a new analytical method for quantifying the total 3,3',5-triiodo-l-thyronine (TT3), total 3,3',5,5'-tetraiodo-l-thyronine (TT4), 3,3',5'-triiodo-l-thyronine, and reverse T3 (rT3) levels using LC-MS/MS. Repeatability and reproducibility with coefficient of variation values of 2-9 and 3-13%, respectively, were acceptable, suggesting that the assay was suitable for measuring serum THs. We measured the serum TH levels of patients with DS but without thyroid dysfunction (age, 3-20 years) and compared the levels to those of controls (patients with idiopathic short stature; age, 3-17 years). When TH levels were summarized by age group, the serum TT4 concentrations were not significantly different between the controls and patients with DS across all age groups. Meanwhile, the serum TT3 concentrations differed according to age. In addition, the serum rT3 concentrations were significantly higher in patients with DS than in controls, except for those in the 12-14 age group. We also calculated the T3/T4 and rT3/T4 ratios to elucidate the reason for the higher rT3 in patients with DS; however, no useful findings were obtained. Thus, further investigation is needed to clarify our findings.
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http://dx.doi.org/10.1002/bmc.5249DOI Listing
January 2022

A case of hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome with kidney failure and recurrent pancreatitis: Answers.

Pediatr Nephrol 2020 Dec 29;36(12):4071-4075. Epub 2021 Jul 29.

Department of Nephrology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan.

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http://dx.doi.org/10.1007/s00467-021-05190-wDOI Listing
December 2020

A case of hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome with kidney failure and recurrent pancreatitis: Questions.

Pediatr Nephrol 2020 Dec 29;36(12):4067-4069. Epub 2021 Jul 29.

Department of Nephrology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan.

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http://dx.doi.org/10.1007/s00467-021-05183-9DOI Listing
December 2020

Very long-chain acyl-CoA dehydrogenase deficiency: No developmental delay after cardiopulmonary arrest.

Pediatr Int 2021 Aug 29;63(8):992-994. Epub 2021 Jun 29.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

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http://dx.doi.org/10.1111/ped.14666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457193PMC
August 2021

A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2.

J Hum Genet 2021 Nov 24;66(11):1121-1126. Epub 2021 May 24.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects.
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http://dx.doi.org/10.1038/s10038-021-00937-7DOI Listing
November 2021

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia.

Calcif Tissue Int 2021 05 23;108(5):622-633. Epub 2021 Jan 23.

Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.
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http://dx.doi.org/10.1007/s00223-020-00797-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064984PMC
May 2021

Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages.

Hepatol Commun 2021 01 26;5(1):52-62. Epub 2020 Sep 26.

Laboratory of Molecular Pharmacokinetics Graduate School of Pharmaceutical Sciences University of Tokyo Tokyo Japan.

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An mutagenesis assay to evaluate pathogenicity of mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. : CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.
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http://dx.doi.org/10.1002/hep4.1605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789840PMC
January 2021

Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46,XX ovotesticular disorder of sex development.

Am J Med Genet A 2021 04 5;185(4):1067-1075. Epub 2021 Jan 5.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

SOX9, a transcription factor, is expressed in the undifferentiated XX and XY gonads. SRY induces significant upregulation of SOX9 expression in XY gonads. Loss-of-function SOX9 variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain-of-function (GoF) SOX9 variants have not been reported previously. We report the case of a 16-year-old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next-generation sequencing-based genetic screening for disorders of sex development led to the identification of a novel SOX9 variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K-SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype-SOX9. This GoF activity was not observed in the luciferase reporter containing Amh, the gene for anti-Müllerian hormone. We genetically engineered female mice (Sox9 ), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel SOX9 variant with a promoter-specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF SOX9 variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.
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http://dx.doi.org/10.1002/ajmg.a.62063DOI Listing
April 2021

Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.

Endocr J 2021 Apr 21;68(4):399-407. Epub 2020 Nov 21.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.
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http://dx.doi.org/10.1507/endocrj.EJ20-0325DOI Listing
April 2021

Screening for imprinting disorders in 58 patients with clinically diagnosed idiopathic short stature.

J Pediatr Endocrinol Metab 2020 Aug 31;33(10):1335-1339. Epub 2020 Aug 31.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Objectives Imprinted genes have important roles for normal growth and development. Imprinting disorders (IDs) such as Silver-Russell syndrome and Temple syndrome are rare diseases that typically cause short children born small for gestational age (SGA). However, some patients with short stature (SS) caused by IDs were born non-SGA. To date, the contribution of IDs to idiopathic short stature (ISS) has been poorly investigated. The aim of this study was to clarify the contribution of IDs to ISS. Methods We conducted methylation analysis for 10 differentially methylated regions using pyrosequencing to detect known IDs in 58 patients (31 male and 27 female children, height standard deviation score -4.2 to -2.0) carrying a clinical diagnosis of ISS. Results We identified no patient with IDs among these patients with ISS. Conclusions These results indicate that IDs are rare in patients having ISS, and that imprinted genes affect fetal growth more than postnatal growth. Because patients with IDs born non-SGA usually have clinical features characteristic of each ID, in addition to SS, the patients with ISS as a clinical diagnosis may not be associated with IDs. It is unlikely that cases clinically diagnosed with ISS are caused by IDs leading to growth failure.
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http://dx.doi.org/10.1515/jpem-2020-0198DOI Listing
August 2020

Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Context: PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain.

Objective: We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain.

Methods: Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1.

Results: Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction.

Conclusions: Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.
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http://dx.doi.org/10.1210/clinem/dgaa584DOI Listing
November 2020

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency.

Sci Rep 2020 07 3;10(1):10985. Epub 2020 Jul 3.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.
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http://dx.doi.org/10.1038/s41598-020-67715-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335161PMC
July 2020

Correction to: Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

CEN Case Rep 2020 Aug;9(3):294

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa, 2‑138‑4, Minami‑ku, Yokohama, 232‑8555, Japan.

In the Original publication of the article, there are two minor errors in Fig. 2 and these include one missing arrow in Fig. 2d and appears as an incorrectly drawn solid lines as dashed line in Fig. 2d.
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http://dx.doi.org/10.1007/s13730-020-00477-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320077PMC
August 2020

A nationwide questionnaire survey targeting Japanese pediatric endocrinologists regarding transitional care in childhood, adolescent, and young adult cancer survivors.

Clin Pediatr Endocrinol 2020 16;29(2):55-62. Epub 2020 Apr 16.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.
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http://dx.doi.org/10.1297/cpe.29.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160455PMC
April 2020

Novel biallelic mutations alter the skeletal phenotype of 3M syndrome.

Hum Genome Var 2020 4;7. Epub 2020 Feb 4.

1Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.

3M syndrome is an autosomal recessive disorder characterized by severe growth retardation, distinct facial features, and skeletal changes, including long slender tubular bones and tall vertebral bodies. We report a Japanese patient with 3M syndrome caused by the biallelic novel variants c.1705_1708del and c.1989_1999del of . Skeletal features were consistent with 3M syndrome in the early neonatal period but became less obvious by 2 years of age.
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http://dx.doi.org/10.1038/s41439-020-0090-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000808PMC
February 2020

Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

CEN Case Rep 2020 05 3;9(2):133-137. Epub 2020 Jan 3.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa, 2-138-4, Minami-ku, Yokohama, 232-8555, Japan.

Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC γ-subunit gene mutations via a retrospective chart review; reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity. The serum potassium level decreased from 5.6 to 4.5 mEq/L. Next, we attempted to elucidate the pathophysiological basis of the usefulness of potassium restriction, leveraged by the increased knowledge regarding the roles of with-no-lysine kinases (WNKs) in the distal nephron. When potassium is restricted, the WNK signal will turn "on" in the distal nephron via reduction in the intracellular chloride level. Consequently, the sodium reabsorption from the NaCl cotransporter (NCC) in the distal convoluted tubule and possibly from pendrin in the β-intercalated cell will increase. Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct. In conclusion, dietary potassium restriction is one of the indispensable treatments for generalized PHA1.
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http://dx.doi.org/10.1007/s13730-019-00441-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148393PMC
May 2020

Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review.

J Clin Endocrinol Metab 2019 12;104(12):6229-6237

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Context: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified.

Objectives: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations.

Patients And Methods: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed.

Results: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap.

Conclusions: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.
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http://dx.doi.org/10.1210/jc.2019-00657DOI Listing
December 2019

SHOX far-downstream copy-number variations involving cis-regulatory nucleotide variants in two sisters with Leri-Weill dyschondrosteosis.

Am J Med Genet A 2019 09 22;179(9):1778-1782. Epub 2019 Jun 22.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

SHOX haploinsufficiency leading to Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature typically results from intragenic mutations or copy-number variations (CNVs) involving SHOX and/or its putative enhancer regions that are distributed in the genomic interval between 400 kb and 840 kb from Xpter/Ypter. Here, we report two sisters with LWD, who carried a deletion in the far-downstream region of SHOX. The 0.62 Mb deletion contained 50 single nucleotide polymorphisms (SNPs) and short insertions and deletions (indels), whose genotypes were linked to SHOX expression levels in the Genotype-Tissue Expression portal. Notably, most of these SNPs/indels accumulated within a ~20 kb interval that was positioned ~900 kb away from Xpter/Ypter. These SNPs/indels showed similar minor allele frequencies, indicating that they reside within a haplotype block. The ~20 kb interval was not evolutionarily conserved; however, it was associated with the previously determined peak of chromosome conformation capture profiling (4C)-seq. Importantly, the deletion in the present cases partially overlapped with CNVs of three previous cases with skeletal deformity and/or short stature. The results indicate that far-downstream CNVs constitute rare genetic causes of SHOX haploinsufficiency. These CNVs possibly impair SHOX expression through copy-number changes of a human-specific cis-regulatory haplotype block. This notion awaits further validation.
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http://dx.doi.org/10.1002/ajmg.a.61275DOI Listing
September 2019

DNA Methylation Status of SHOX-Flanking CpG Islands in Healthy Individuals and Short Stature Patients with Pseudoautosomal Copy Number Variations.

Cytogenet Genome Res 2019 4;158(2):56-62. Epub 2019 Jun 4.

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.
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http://dx.doi.org/10.1159/000500468DOI Listing
September 2019

Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.

Lancet 2019 06 16;393(10189):2416-2427. Epub 2019 May 16.

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International.
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http://dx.doi.org/10.1016/S0140-6736(19)30654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179969PMC
June 2019

Severe in utero under-virilization in a 46,XY patient with Silver-Russell syndrome with 11p15 loss of methylation.

J Pediatr Endocrinol Metab 2019 Feb;32(2):191-196

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.
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http://dx.doi.org/10.1515/jpem-2018-0464DOI Listing
February 2019

Analysis of mutations via protein expression studies in glycogen storage disease type IV: A report on a non-progressive form with a literature review.

Mol Genet Metab Rep 2018 Dec 13;17:31-37. Epub 2018 Sep 13.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan.

Background: Glycogen storage disease type IV (GSD IV), caused by mutations, has a quite wide phenotypic variation. While the classic hepatic form and the perinatal/neonatal neuromuscular forms result in early mortality, milder manifestations include non-progressive form (NP-GSD IV) and adult polyglucosan body disease (APBD). Thus far, only one clinical case of a patient with compound heterozygous mutations has been reported for the molecular analysis of NP-GSD IV. This study aimed to elucidate the molecular basis in a NP-GSD IV patient via protein expression analysis and to obtain a clearer genotype-phenotype relationship in GSD IV.

Case Presentation: A Japanese boy presented hepatosplenomegaly at 2 years of age. Developmental delay, neurological symptoms, and cardiac dysfunction were not apparent. Observation of hepatocytes with periodic acid-Schiff-positive materials resistant to diastase, coupled with resolution of hepatosplenomegaly at 8 years of age, yielded a diagnosis of NP-GSD IV. Glycogen branching enzyme activity was decreased in erythrocytes. At 13 years of age, he developed epilepsy, which was successfully controlled by carbamazepine.

Molecular Analysis: In this study, we identified compound heterozygous mutations (p.Gln46Pro and p.Glu609Lys). The branching activities of the mutant proteins expressed using were examined in a reaction with starch. The result showed that both mutants had approximately 50% activity of the wild type protein.

Conclusion: This is the second clinical report of a NP-GSD IV patient with a definite molecular elucidation. Based on the clinical and genotypic overlapping between NP-GSD IV and APBD, we suggest both are in a continuum.
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http://dx.doi.org/10.1016/j.ymgmr.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140619PMC
December 2018

Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review.

Endocr J 2018 Dec 15;65(12):1187-1192. Epub 2018 Sep 15.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.

A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.
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http://dx.doi.org/10.1507/endocrj.EJ18-0218DOI Listing
December 2018

Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias.

Cytogenet Genome Res 2018 7;154(3):122-125. Epub 2018 Apr 7.

Isodicentric Y chromosome [idic(Y)] represents a relatively common subtype of Y chromosomal rearrangements in the germline; however, limited evidence supports the postzygotic occurrence of idic(Y). Here, we report a boy with hypospadias and somatically acquired idic(Y). The 3.5-year-old boy has been identified in our previous study for patients with hypospadias. In the present study, cytogenetic analysis including FISH revealed a 45,X[5]/46,X,idic(Y)[7]/46,XY[8] karyotype. MLPA showed a mosaic deletion involving PPP1R12BP1 and RBMY2DP. The idic(Y) was likely to have been formed through aberrant recombination between P1 palindromes and subsequently underwent mosaic loss. The patient's phenotype was attributable to deletion of some Y chromosomal genes and/or mosaic loss of chromosome Y (mLOY). The results suggest that idic(Y) can originate in postzygotic cells via palindrome-mediated crossovers. Moreover, our data indicate that somatically acquired idic(Y) can trigger mLOY, which usually appears as an aging-related phenomenon in elderly men.
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http://dx.doi.org/10.1159/000488162DOI Listing
May 2018

A case of paternal uniparental isodisomy for chromosome 7 associated with overgrowth.

J Med Genet 2018 08 17;55(8):567-570. Epub 2018 Feb 17.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: Paternal uniparental disomy for chromosome 7 (upd(7)pat) is extremely rare, and only four cases have been previously reported. As these cases were accompanied by autosomal-recessive disorders which are likely to be involved in growth restriction, the relevance of upd(7)pat to the overgrowth phenotype remains unclear. Here we describe one case of upd(7)pat with no additional genetic diseases, which may answer the question.

Methods: A 5-year-old Japanese boy presented with a tall stature of unknown causes. To detect the genetic cause of the tall stature, we performed Sanger sequencing, targeted resequencing, comparative genomic hybridisation and single-nucleotide polymorphism (SNP) array analyses, methylation analysis and microsatellite analysis.

Results: We could not detect pathogenic variants in causative genes for overgrowth syndrome or apparent copy number alterations. DNA methylation analysis revealed hypomethylation at the , and differentially methylated regions. SNP array and microsatellite analyses suggested paternal uniparental isodisomy for chromosome 7. Furthermore, we could not identify homozygous mutations of known causative genes for inherited disorders on chromosome 7.

Conclusion: We report the first case of upd(7)pat with an overgrowth phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2017-104986DOI Listing
August 2018

Fluctuation of blood glucose levels in an infant with an ileostomy on continuous glucose monitoring: A case report.

Clin Pediatr Endocrinol 2018 30;27(1):39-43. Epub 2018 Jan 30.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Infants with an ileostomy can be at high risk of hypoglycemia because of inadequate nutritional intake; however, there are no reports investigating blood glucose (BG) in infants with ileostomy. We experienced a case of an extremely low birth weight infant who was born at 24 wk of gestation and weighted 623 g. He received an ileostomy because of an intestinal perforation. After the ileostomy, he had recurrent hypoglycemia. Continuous glucose monitoring showed fluctuation of BG levels (postprandial BG elevations and subsequent declines) and non-fasting hypoglycemia, which were undetectable with intermittent fasting BG measurement. The fluctuation of BG levels and non-fasting hypoglycemia improved after closure of the ileostomy. Patients with ileostomy may present with hypoglycemia that is undetectable with intermittent fasting BG measurement. In this case, continuous glucose monitoring was very useful for detecting fluctuation of BG levels and hypoglycemic episodes. Therefore, we recommend that continuous glucose monitoring be performed in infants with an ileostomy to confirm whether they have hypoglycemia or a fluctuation in BG levels. Further studies on the postprandial dynamics of various hormones in infants with ileostomy are required.
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http://dx.doi.org/10.1297/cpe.27.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792820PMC
January 2018

Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages.

EBioMedicine 2018 Jan 7;27:187-199. Epub 2017 Oct 7.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Progressive familial intrahepatic cholestasis type 1 (PFIC1), a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. Because of the difficulty of discriminating PFIC1 from other subtypes of PFIC based on its clinical and histological features and genome sequencing, an alternative method for diagnosing PFIC1 is desirable. Herein, we analyzed human peripheral blood monocyte-derived macrophages (HMDM) and found predominant expression of ATP8B1 in interleukin-10 (IL-10)-induced M2c, a subset of alternatively activated macrophages. SiRNA-mediated depletion of ATP8B1 in IL-10-treated HMDM markedly suppressed the expression of M2c-related surface markers and increased the side scatter (SSC) of M2c, likely via impairment of the IL-10/STAT3 signal transduction pathway. These phenotypic features were confirmed in IL-10-treated HMDM from four PFIC1 patients with disease-causing mutations in both alleles, but not in those from four patients with other subtypes of PFIC. This method identified three PFIC1 patients in a group of PFIC patients undiagnosed by genome sequencing, an identical diagnostic outcome to that achieved by analysis of liver specimens and in vitro mutagenesis studies. In conclusion, ATP8B1 deficiency caused incomplete polarization of HMDM into M2c. Phenotypic analysis of M2c helps to identify PFIC1 patients with no apparent disease-causing mutations in ATP8B1.
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http://dx.doi.org/10.1016/j.ebiom.2017.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828058PMC
January 2018

Association between monoallelic mutations and congenital hypothyroidism: a statistical approach.

Eur J Endocrinol 2018 Feb 1;178(2):137-144. Epub 2017 Nov 1.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Objective: Biallelic mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor.

Subjects And Methods: We enrolled 395 patients that had a positive result in NBS and sequenced Monoallelic mutation carriers were further sequenced for . Molecular functions of the mutations were verified . The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes' theorem, we estimated a posterior probability of NBS positivity given the mutation.

Results: Twenty-six monoallelic mutation carriers were found. Four out of the 26 also had a monoallelic mutation (double heterozygotes). The frequencies of monoallelic mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic mutation carriers and 3.8% in double heterozygotes.

Conclusions: Monoallelic mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic mutations.
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http://dx.doi.org/10.1530/EJE-16-1049DOI Listing
February 2018

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.

Endocr J 2017 Oct 3;64(10):947-954. Epub 2017 Aug 3.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.
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http://dx.doi.org/10.1507/endocrj.EJ17-0150DOI Listing
October 2017

Additional report on Moreno-Nishimura-Schmidt overgrowth syndrome.

Am J Med Genet A 2017 Oct 25;173(10):2834-2837. Epub 2017 Jul 25.

Department of Radiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1002/ajmg.a.38368DOI Listing
October 2017
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