Journal of Personalized Medicine

Research

13 pages, 1696 KiB

Open AccessArticle

Effects of Androgen Treatment on Growth in Patients with 5-α-Reductase Type 2 Deficiency

by Hae In Lee, Sujin Kim, Sang-woon Kim, Myeongseob Lee, Kyungchul Song, Junghwan Suh, Yong Seung Lee, Hyun Wook Chae, Ho-Seong Kim, Sangwon Han and Ahreum Kwon

J. Pers. Med. 2023, 13(6), 992; https://doi.org/10.3390/jpm13060992 - 13 Jun 2023

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Abstract

Background: Patients with 5-α-reductase type 2 deficiency (5αRD2) require androgen treatment for the growth of normal male external genitalia. Since limited research has been conducted on the effects of androgen treatment on height in individuals with 5αRD2, we investigated the effect of androgen [...] Read more.

Background: Patients with 5-α-reductase type 2 deficiency (5αRD2) require androgen treatment for the growth of normal male external genitalia. Since limited research has been conducted on the effects of androgen treatment on height in individuals with 5αRD2, we investigated the effect of androgen treatment on bone age (BA) and the height status in children with 5αRD2. Methods: Of the 19 participants who were followed up for an average of 10.6 years, 12 received androgen treatment. BA and height standard deviation scores (SDS) were compared between the treatment and non-treatment groups, as well as between the dihydrotestosterone (DHT) and testosterone enanthate (TE) treatment groups. Results: Despite the above-average height of the 19 patients with 5αRD2, the height SDS relative to BA (htSDS-BA) was below average, particularly in the androgen treatment group. DHT treatment did not lead to an increase in BA or htSDS-BA, whereas TE treatment resulted in BA advancement and decreased htSDS-BA, especially in the prepubertal period. Conclusions: DHT treatment is more favorable for height than TE treatment in patients with 5αRD2, particularly during the prepubertal period. Therefore, age and the type of androgen used should be carefully considered to minimize the risk of height reduction in these patient groups. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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9 pages, 2010 KiB

Open AccessArticle

Landscape of Secondary Findings in Chinese Population: A Practice of ACMG SF v3.0 List

by Yingzhao Huang, Bowen Liu, Jile Shi, Sen Zhao, Kexin Xu, Liying Sun, Na Chen, Wen Tian, Jianguo Zhang and Nan Wu

J. Pers. Med. 2022, 12(9), 1503; https://doi.org/10.3390/jpm12091503 - 14 Sep 2022

Cited by 1 | Viewed by 1907

Abstract

Clinical exome sequencing (CES) has shown great utility in the diagnosis of Mendelian disorders. CES can unravel secondary findings (SFs) unrelated to the primary diagnosis but with potential health implications. The American College of Medical Genetics and Genomics (ACMG) has published a guideline [...] Read more.

Clinical exome sequencing (CES) has shown great utility in the diagnosis of Mendelian disorders. CES can unravel secondary findings (SFs) unrelated to the primary diagnosis but with potential health implications. The American College of Medical Genetics and Genomics (ACMG) has published a guideline for reporting secondary findings and recently updated an ACMG SF v3.0 list comprising 73 genes. Several studies have been performed to explore the prevalence of SFs. However, the data were limited in the Chinese population. In this study, we evaluated the genetic data of 2987 individuals from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group in accordance with the ACMG SF v3.0 list. The detected variants were evaluated using the ACMG classification guidelines, HGMD, and ClinVar database. Totally, 157 (157/2987, 5.3%) individuals had reportable variants within genes associated with cancer, cardiovascular, metabolic, and miscellaneous phenotypes. We identified 63 known pathogenic (KP) variants in 72 individuals (72/2987, 2.4%) and 96 expected pathogenic (EP) variants in 105 individuals (3.5%). Forty-five individuals carried SFs in v3.0 newly added genes, which accounted for 1.5% of our cohort. Our findings could contribute to existing knowledge of secondary findings in different ethnicities and indicate the necessity for clinicians to update the SFs gene list. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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14 pages, 4545 KiB

Open AccessArticle

Growth Curves of Chinese Children with Androgen Insensitivity Syndrome: A Multicenter Registry Study

by Xiu Zhao, Zhe Su, Shaoke Chen, Xiumin Wang, Yu Yang, Linqi Chen, Li Liang, Geli Liu, Yi Wang, Yanning Song, Lijun Fan, Xiaoya Ren and Chunxiu Gong

J. Pers. Med. 2022, 12(5), 771; https://doi.org/10.3390/jpm12050771 - 10 May 2022

Cited by 1 | Viewed by 1686

Abstract

Objective: To provide new information about androgen insensitivity syndrome (AIS), we studied growth patterns in Chinese children with AIS. Subjects: Data are from 118 untreated AIS patients who were admitted to eight pediatric endocrine centers from January 2010 to December 2019. Methods: In [...] Read more.

Objective: To provide new information about androgen insensitivity syndrome (AIS), we studied growth patterns in Chinese children with AIS. Subjects: Data are from 118 untreated AIS patients who were admitted to eight pediatric endocrine centers from January 2010 to December 2019. Methods: In this retrospective cohort study, clinical data were collected from a multicenter database. We compared physical assessment data among AIS patients and standard growth charts for Chinese pediatric population. Results: 1. Children with AIS grew slightly less than the mean before 6 months of age, and then, height gradually increased before 12 years of age, from the median to +1 standard deviation (SD), according to the standard reference for Chinese pediatric population. After 12 years of age, height showed differently in profiles: The mean height in AIS patients gradually decreased from the mean to −1 SD, according to the standard for Chinese boys, and increased from the mean to +2 SD, according to the standard for Chinese girls. 2. The weights of children with AIS were greater than the mean standards of Chinese pediatric population from newborn to 11 years of age. From 12–16 years of age, the mean weight of children with AIS showed different profiles, from the mean to −1 SD, according to the standard for Chinese boys and from the mean to +1.5 SD, according to the standard for Chinese girls. 3. Weight standard deviation (WtSDS) and target height (THt) in northern Chinese AIS patients were significantly higher than those from the southern region (p = 0.035, 0.005, respectively). Age in northern Chinese AIS patients was significantly younger than those from the southern region (p = 0.034). No difference was found among birth weight (BW), birth length (BL), height standard deviation (HtSDS) and body mass index (BMI) in AIS patients from different regions (p > 0.05). 4. HtSDS and WtSDS in complete AIS (CAIS) patients were higher than those in partial AIS (PAIS) patients without significant difference (p > 0.05). Conclusions: Growth of children with AIS varied to different degrees. AIS patients seemed not to experience a puberty growth spurt. CAIS and PAIS patients show little difference in their growth. Regional differences have no effect on the height but influence the weight of AIS patients. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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12 pages, 1556 KiB

Open AccessArticle

Genetic and Phenotypic Spectrum of KBG Syndrome: A Report of 13 New Chinese Cases and a Review of the Literature

by Fenqi Gao, Xiu Zhao, Bingyan Cao, Xin Fan, Xiaoqiao Li, Lele Li, Shengbin Sui, Zhe Su and Chunxiu Gong

J. Pers. Med. 2022, 12(3), 407; https://doi.org/10.3390/jpm12030407 - 05 Mar 2022

Cited by 6 | Viewed by 4553

Abstract

KBG syndrome (KBGS) is a rare autosomal dominant inherited disease that involves multiple systems and is associated with variations in the ankyrin repeat domain 11 (ANKRD11) gene. We report the clinical and genetic data for 13 Chinese KBGS patients diagnosed by [...] Read more.

KBG syndrome (KBGS) is a rare autosomal dominant inherited disease that involves multiple systems and is associated with variations in the ankyrin repeat domain 11 (ANKRD11) gene. We report the clinical and genetic data for 13 Chinese KBGS patients diagnosed by genetic testing and retrospectively analyse the genotypes and phenotypes of previously reported KBGS patients. The 13 patients in this study had heterozygous variations in the ANKRD11 gene, including seven frameshift variations, three nonsense variations, and three missense variations. They carried 11 variation sites, of which eight were previously unreported. The clinical phenotype analysis of these 13 patients and 240 previously reported patients showed that the occurrence rates of craniofacial anomalies, dental anomalies, global developmental delays, intellectual disability/learning difficulties, limb anomalies, and behavioural anomalies were >70%. The occurrence rates of short stature, delayed bone age, and spinal vertebral body anomalies were >50%. The frequency of global developmental delays and intellectual disability/learning difficulties in patients with truncated ANKRD11 gene variation was higher than that in patients with missense variation in the ANKRD11 gene (p < 0.05). Collectively, this study reported the genotypic and phenotypic characteristics of the largest sample of KBGS patients from China and discovered eight new ANKRD11 gene variations, which enriched the variation spectrum of the ANKRD11 gene. Variation in the ANKRD11 gene mainly caused craniofacial anomalies, growth and developmental anomalies, skeletal system anomalies, and nervous system anomalies. Truncated variation in the ANKRD11 gene is more likely to lead to global growth retardation and intellectual disability/learning difficulties than missense variation in ANKRD11. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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14 pages, 2616 KiB

Open AccessArticle

Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model

by Jing Deng, Xin-Xin Guan, Ying-Bao Zhu, Hai-Tao Deng, Guang-Xu Li, Yi-Chen Guo, Peng Jin, Ran-Hui Duan and Wen Huang

J. Pers. Med. 2022, 12(3), 385; https://doi.org/10.3390/jpm12030385 - 02 Mar 2022

Cited by 3 | Viewed by 2201

Abstract

Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs [...] Read more.

Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-β pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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13 pages, 1256 KiB

Open AccessArticle

Application of Whole Exome Sequencing and Functional Annotations to Identify Genetic Variants Associated with Marfan Syndrome

by Min-Rou Lin, Che-Mai Chang, Jafit Ting, Jan-Gowth Chang, Wan-Hsuan Chou, Kuei-Jung Huang, Gloria Cheng, Hsiao-Huang Chang and Wei-Chiao Chang

J. Pers. Med. 2022, 12(2), 198; https://doi.org/10.3390/jpm12020198 - 01 Feb 2022

Cited by 3 | Viewed by 2064

Abstract

Marfan syndrome (MFS) is a rare disease that affects connective tissue, which causes abnormalities in several organ systems including the heart, eyes, bones, and joints. The autosomal dominant disorder was found to be strongly associated with FBN1, TGFBR1, and TGFBR2 mutations. [...] Read more.

Marfan syndrome (MFS) is a rare disease that affects connective tissue, which causes abnormalities in several organ systems including the heart, eyes, bones, and joints. The autosomal dominant disorder was found to be strongly associated with FBN1, TGFBR1, and TGFBR2 mutations. Although multiple genetic mutations have been reported, data from Asian populations are still limited. As a result, we utilized the whole exome sequencing (WES) technique to identify potential pathogenic variants of MFS in a Taiwan cohort. In addition, a variety of annotation databases were applied to identify the biological functions as well as the potential mechanisms of candidate genes. In this study, we confirmed the pathogenicity of FBN1 to MFS. Our results indicated that TTN and POMT1 may be likely related to MFS phenotypes. Furthermore, we found nine unique variants highly shared in a MFS family cohort, of which eight are novel variants worthy of further investigation. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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12 pages, 590 KiB

Open AccessArticle

Cell-Free DNA Screening for Sex Chromosome Abnormalities and Pregnancy Outcomes, 2018–2020: A Retrospective Analysis

by Yanmei Lu, Shihao Zhou, Siyuan Linpeng, Siyi Ding, Shihong Li, Yujiao Li, Liangcheng Shi, Jun He and Yalan Liu

J. Pers. Med. 2022, 12(1), 48; https://doi.org/10.3390/jpm12010048 - 04 Jan 2022

Cited by 7 | Viewed by 3622

Abstract

To evaluate the efficacy of non-invasive prenatal screening (NIPT) for detecting fetal sex chromosome abnormalities, a total of 639 women carrying sex chromosome abnormalities were selected from 222,107 pregnant women who participated in free NIPT from April 2018 to December 2020. The clinical [...] Read more.

To evaluate the efficacy of non-invasive prenatal screening (NIPT) for detecting fetal sex chromosome abnormalities, a total of 639 women carrying sex chromosome abnormalities were selected from 222,107 pregnant women who participated in free NIPT from April 2018 to December 2020. The clinical data, prenatal diagnosis results, and follow-up pregnancy outcomes of participants were collected. The positive predictive value (PPV) was used to analyze the performance of NIPT. Around 235 cases were confirmed with sex chromosome abnormalities, including 229 cases with sex chromosome aneuploidy (45, X (n = 37), 47, XXX (n = 37), 47, XXY (n = 110), 47, XYY (n = 42)) and 6 cases with structural abnormalities. The total incidence rate was 0.11% (235/222,107). The PPV of NIPT was 45.37% (235/518). NIPT accuracy for detecting sex chromosome polysomes was higher than that for sex chromosome monomers. The termination of pregnancy rate for fetal diagnosis of 45, X, and 47, XXY was higher than that of 47, XXX, and 47, XYY. The detection rate of fetal sex chromosome abnormalities was higher in 2018–2020 than in 2010–2012 (χ² = 69.708, P < 2.2 × 10⁻¹⁶), indicating that NIPT is greatly efficient to detect fetal sex chromosome abnormalities. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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9 pages, 1278 KiB

Open AccessArticle

Reanalysis of Exome Data Identifies Novel SLC25A46 Variants Associated with Leigh Syndrome

by Qifei Li, Jill A. Madden, Jasmine Lin, Jiahai Shi, Samantha M. Rosen, Klaus Schmitz-Abe and Pankaj B. Agrawal

J. Pers. Med. 2021, 11(12), 1277; https://doi.org/10.3390/jpm11121277 - 02 Dec 2021

Cited by 5 | Viewed by 2216

Abstract

SLC25A46 (solute carrier family 25 member 46) mutations have been linked to various neurological diseases with recessive inheritance, including Leigh syndrome, optic atrophy, and lethal congenital pontocerebellar hypoplasia. SLC25A46 is expressed in the outer membrane of mitochondria, where it plays a critical role [...] Read more.

SLC25A46 (solute carrier family 25 member 46) mutations have been linked to various neurological diseases with recessive inheritance, including Leigh syndrome, optic atrophy, and lethal congenital pontocerebellar hypoplasia. SLC25A46 is expressed in the outer membrane of mitochondria, where it plays a critical role in mitochondrial dynamics. A deceased 7-month-old female infant was suspected to have Leigh syndrome. Clinical exome sequencing was non-diagnostic, but research reanalysis of the sequencing data identified two novel variants in SLC25A46: a missense (c.1039C>T, p.Arg347Cys; NM_138773, hg19) and a donor splice region variant (c.283+5G>A) in intron 1. Both variants were predicted to be damaging. Sanger sequencing of cDNA detected a single missense allele in the patient compared to control, and the SLC25A46 transcript levels were also reduced due to the splice region variant. Additionally, Western blot analysis of whole-cell lysate showed a decrease of SLC25A46 expression in proband fibroblasts, relative to control cells. Further, analysis of mitochondrial morphology revealed evidence of increased fragmentation of the mitochondrial network in proband fibroblasts, compared to control cells. Collectively, our findings suggest that these novel variants in SLC24A46, the donor splice one and the missense variant, are the cause of the neurological phenotype in this proband. Full article

(This article belongs to the Special Issue Rare and Orphan Disorders: An Emerging Challenge)

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