Article
Genetics & Heredity
Kheloud M. Alhamoudi, Balgees Alghamdi, Abeer Aljomaiah, Meshael Alswailem, Hindi Al-Hindi, Ali S. Alzahrani
Summary: A young girl with 46,XY DSD was found to have a unique novel mutation in the NR5A1 gene, resulting in severe gonadal dysgenesis and deficiency of testosterone and anti-Mullerian hormone secretion. Despite the atrophied testes and lack of breast development, the patient identified as female and responded well to estrogen/progesterone therapy, showing excellent breast development and normal cyclical menses. This case demonstrates the importance of a genetic mutation in explaining the clinical phenotype of DSD.
FRONTIERS IN GENETICS
(2022)
Review
Endocrinology & Metabolism
Maeva Elzaiat, Ken McElreavey, Anu Bashamboo
Summary: This article discusses the etiology of 46,XY gonadal dysgenesis (GD), evaluates known and unknown genes through functional studies, and proposes recommendations for interpreting data and establishing causality.
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Review
Genetics & Heredity
Wei Zhang, Jiangfeng Mao, Xi Wang, Bang Sun, Zhiyuan Zhao, Xiaoxia Zhang, Min Nie, Xueyan Wu
Summary: In this study, the molecular cause of a patient with syndromic 46, XY disorders/differences of sex development (DSD) was identified as compound heterozygous variants in PPP2R3C. Further analysis revealed that PPP2R3C mutations are associated with specific syndromic 46, XY gonadal dysgenesis, which includes multiple extragonadal anomalies. The findings expand the understanding of PPP2R3C pathogenic variants and the associated clinical manifestations.
FRONTIERS IN GENETICS
(2022)
Article
Endocrinology & Metabolism
Nathalia Lisboa Gomes, Rafael Loch Batista, Mirian Y. Nishi, Antonio Marcondes Lerario, Thatiana E. Silva, Amanda de Moraes Narcizo, Anna Flavia Figueredo Benedetti, Mariana Ferreira de Assis Funari, Jose Antonio Faria Junior, Daniela Rodrigues Moraes, Lia Mesquita Lousada Quintao, Luciana Ribeiro Montenegro, Maria Teresa Martins Ferrari, Alexander A. Jorge, Ivo J. P. Arnhold, Elaine Maria Frade Costa, Sorahia Domenice, Berenice Bilharinho Mendonca
Summary: The combination of clinical/biochemical and genetic approaches significantly improves the diagnosis of 46,XY DSD, and MPS as a first-line approach helps simplify the diagnostic workflow.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Article
Biology
Felipe Rodrigues de Oliveira, Tais Nitsch Mazzola, Maricilda Palandi de Mello, Ana Paula Francese-Santos, Sofia Helena V. de Lemos-Marini, Andrea Trevas Maciel-Guerra, Olaf Hiort, Ralf Werner, Gil Guerra-Junior, Helena Fabbri-Scallet
Summary: The group of disorders known as 46,XY gonadal dysgenesis (GD) includes complete and partial GD (PGD) and testicular regression syndrome (TRS). DHX37 gene variants were identified as a cause of PGD and TRS, indicating its importance in sex development disorders. Variants in DHX37 were found in 4 out of 25 individuals with 46,XY DSD, suggesting a potential role of DHX37 in testis development.
Article
Genetics & Heredity
T. S. Ragitha, K. S. Sunish, Sareena Gilvaz, Saley Daniel, P. R. Varghese, Soumya Raj, Jijo Francis, R. Suresh Kumar
Summary: Developmental disruption of the Mullerian duct and gonads in females can lead to Mullerian agenesis and gonadal dysgenesis, which are classified as 46,XX Disorders of Sexual Development (DSD). The role of WNT4 gene in Indian 46,XX DSD patients with Mullerian agenesis and/or Gonadal dysgenesis was analyzed, but no evidence of WNT4 involvement in the disease condition was found.
Article
Obstetrics & Gynecology
Arvand Akbari, Kimiya Padidar, Najmeh Salehi, Mehri Mashayekhi, Navid Almadani, Mohammad Ali Sadighi Gilani, Anu Bashambou, Ken McElreavey, Mehdi Totonchi
Summary: The rare missense variant p. S754L was found in both male and female patients with gonadal failure, indicating a potential impact on protein ATPase activity. This discovery may contribute to genetic counseling and infertility diagnosis and treatment.
HUMAN REPRODUCTION
(2021)
Article
Endocrinology & Metabolism
Maris Laan, Laura Kasak, Kestutis Timinskas, Marina Grigorova, Ceslovas Venclovas, Alexandre Renaux, Tom Lenaerts, Margus Punab
Summary: This study identified the genetic basis of partial gonadal dysgenesis (PGD) in a non-consanguineous family from Estonia, with some patients carrying the NR5A1 c.991-1G > C mutation. Segregation analysis showed incomplete penetrance and phenotypic variability among carriers of this mutation, with possible modulation by rare heterozygous variants inherited from the other parent. The study also identified a likely pathogenic variant SOS1 p.Y136H in another patient, supporting a distinct genetic cause for their condition.
CLINICAL ENDOCRINOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ana Paula Francese-Santos, Jakob A. Meinel, Cristiane S. C. Piveta, Juliana G. R. Andrade, Beatriz A. Barros, Helena Fabbri-Scallet, Vera Lucia Gil-da-Silva-Lopes, Gil Guerra-Junior, Axel Kuenstner, Hauke Busch, Olaf Hiort, Maricilda P. de Mello, Ralf Werner, Andrea T. Maciel-Guerra
Summary: We report a girl with 46,XY partial gonadal dysgenesis who carries a 297 kb duplication at Xp21.2 upstream of the NR0B1 gene. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis. The fine mapping of the breakpoints revealed a tandem duplication of TASL (CXorf21), GK, and partially TAB3.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Brittany Croft, Anthony D. Bird, Makoto Ono, Stefanie Eggers, Stefan Bagheri-Fam, Janelle M. Ryan, Alejandra P. Reyes, Jocelyn van den Bergen, Anne Baxendale, Elizabeth M. Thompson, Andrew J. Kueh, Peter Stanton, Tim Thomas, Andrew H. Sinclair, Vincent R. Harley
Summary: 46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can cause ambiguous genitalia or complete male-to-female sex reversal. It has been found that a variant in FGF9 gene may contribute to the occurrence of GD, and other gene variants can modulate the effects of this FGF9 mutation. These findings provide important insights into the etiology of GD.
Article
Endocrinology & Metabolism
Sukran Poyrazoglu, Firdevs Bas, Birsen Karaman, Melek Yildiz, Seher Basaran, Feyza Darendeliler
Summary: The study evaluated growth data, gonadal functions, and tumor risk in children with 45, X/46, XY mosaicism. Patients showed growth deceleration after 2 years of age, with growth hormone therapy improving adult height. Patients with genital anomalies or female external genitalia had an increased risk of germ cell tumors.
CLINICAL ENDOCRINOLOGY
(2021)
Article
Obstetrics & Gynecology
Pei-Hsiu Yu, Meng-Che Tsai, Chun -Ting Chiang, Han-Yu Wang, Pao-Lin Kuo
Summary: This article reports a case of an 18-year-old phenotypically female with primary amenorrhea. The patient was found to have hypergonadotropic hypogonadism and a novel mutation in the MAP3K1 gene in the karyotype.
TAIWANESE JOURNAL OF OBSTETRICS & GYNECOLOGY
(2022)
Article
Urology & Nephrology
Angie Carolina Carreno-Martinez, Victor Clemente Mendoza Rojas, Julian Arturo Gil Forero, Victor Hugo Figueroa, Gustavo Adolfo Contreras-Garcia
Summary: Mixed gonadal dysgenesis is a common chromosomal abnormality characterized by ambiguous genitalia, with possible presentations of a normal male phenotype, ambiguous genitalia, or features of Turner syndrome. Patients require multidisciplinary evaluation and treatment, including regular monitoring of tumor markers.
UROLOGIA INTERNATIONALIS
(2021)
Review
Pediatrics
Sukanya Priyadarshini, Rajni Sharma
Summary: Disorders of sex development (DSD) refers to congenital conditions where there is a difference in chromosomal, gonadal, or anatomical sex. Pediatricians often encounter the challenge of managing newborns/infants with atypical genitalia or older children with disordered puberty, which fall under the category of DSD. This article provides an updated comprehensive approach to managing DSD, with a focus on atypical genitalia.
INDIAN JOURNAL OF PEDIATRICS
(2023)
Article
Genetics & Heredity
Lili Pan, Zhuoguang Li, Zhe Su, Wei Su, Rongfei Zheng, Weiyan Chen, Xuezhi He, Jianming Song, Shoulin Li, Pengqiang Wen
Summary: The study reported a case of 46, XY gonadal dysgenesis (GD) with minifascicular neuropathy caused by a DHH homozygous variant, and summarized the reported cases worldwide. Furthermore, it revealed multiple complications not previously reported in such cases.
FRONTIERS IN GENETICS
(2022)
Editorial Material
Medical Laboratory Technology
Janae Jones, Rosita Saul, Laila Sathe, Joanna Xie, Dawn Marquette, Valerie A. Arboleda
Summary: By applying the Lean Six Sigma model, the laboratory has successfully increased testing efficiency, reduced errors, increased testing volume, and improved turnaround time.
LABORATORY MEDICINE
(2022)
Article
Biotechnology & Applied Microbiology
Longhua Guo, James Boocock, Evann E. Hilt, Sukantha Chandrasekaran, Yi Zhang, Chetan Munugala, Laila Sathe, Noah Alexander, Valerie A. Arboleda, Jonathan Flint, Eleazar Eskin, Chongyuan Luo, Shangxin Yang, Omai B. Garner, Yi Yin, Joshua S. Bloom, Leonid Kruglyak
Summary: This study uses genome sequencing of SARS-CoV-2 in Los Angeles County to uncover the source of early outbreak strains and the transmission rate. The results indicate that the early outbreak was influenced by multiple introductions from Asia and Europe, and a USA-specific strain was found in the region. This highlights the importance of genome sequencing in investigating outbreaks and informing public health responses.
Article
Biochemical Research Methods
Leroy Bondhus, Roshni Varma, Yenifer Hernandez, Valerie A. Arboleda
Summary: Quantifying the specificity of gene expression is crucial for studying the etiology of genetic diseases, but it remains challenging due to sample similarity. This study demonstrates that incorporating sample similarity information improves the stability of specificity estimates and provides more robust measures for downstream analyses.
BRIEFINGS IN BIOINFORMATICS
(2022)
Article
Biochemistry & Molecular Biology
Zain Awamleh, Eric Chater-Diehl, Sanaa Choufani, Elizabeth Wei, Rebecca R. Kianmahd, Anna Yu, Lauren Chad, Gregory Costain, Wen-Hann Tan, Stephen W. Scherer, Valerie A. Arboleda, Bianca E. Russell, Rosanna Weksberg
Summary: This study identified the unique DNA methylation (DNAm) signature in patients with Bohring-Opitz syndrome (BOS) and the epigenetic dysregulation associated with pathogenic variants in the ASXL gene family. The application of machine learning models and an epigenetic clock improved our understanding of the epigenetic regulatory abnormalities underlying ASXL gene family-associated syndromes.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Developmental Biology
Liang Zhao, Ella Thomson, Ee T. Ng, Enya Longmuss, Terje Svingen, Stefan Bagheri-Fam, Alexander Quinn, Vincent R. Harley, Leonard C. Harrison, Emanuele Pelosi, Peter Koopman
Summary: Sex determination in eutherian mammals is controlled by the Y-linked gene Sry. This study focused on the gene Mmd2, which is expressed during the sex-determining period in male gonads. However, the mice deficient in Mmd2 showed normal testis development, suggesting the possible redundancy of PAQR factors in gonadal development. These findings shed light on the challenges in identifying genes involved in sex determination and may help explain the limited genes associated with disorders/differences of sex development in humans.
SEXUAL DEVELOPMENT
(2023)
Article
Biochemical Research Methods
Leroy Bondhus, Angela Wei, Valerie A. Arboleda
Summary: The study developed a novel method called DMRscaler, which accurately identifies differential DNA methylation regions across a wide range of sizes, from single basepairs to whole chromosomes. The method was able to identify novel regulatory regions in rare-disease cohorts.
BMC BIOINFORMATICS
(2022)
Article
Genetics & Heredity
Ruth Johnson, Yi Ding, Vidhya Venkateswaran, Arjun Bhattacharya, Kristin Boulier, Alec Chiu, Sergey Knyazev, Tommer Schwarz, Malika Freund, Lingyu Zhan, Kathryn S. Burch, Christa Caggiano, Brian Hill, Nadav Rakocz, Brunilda Balliu, Christopher T. Denny, Jae Hoon Sul, Noah Zaitlen, Valerie A. Arboleda, Eran Halperin, Sriram Sankararaman, Manish J. Butte, Clara Lajonchere, Daniel H. Geschwind, Bogdan Pasaniuc
Summary: This study explores the interplay between genetic ancestry and social determinants of health within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative. The researchers find that self-identified race/ethnicity is highly correlated with genetically inferred ancestry, but there are still marked differences between the two. Additionally, the study demonstrates the utility of genetic data linked with electronic health records for performing multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes.
Article
Genetics & Heredity
Brittany Croft, Anthony D. Bird, Makoto Ono, Stefanie Eggers, Stefan Bagheri-Fam, Janelle M. Ryan, Alejandra P. Reyes, Jocelyn van den Bergen, Anne Baxendale, Elizabeth M. Thompson, Andrew J. Kueh, Peter Stanton, Tim Thomas, Andrew H. Sinclair, Vincent R. Harley
Summary: 46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can cause ambiguous genitalia or complete male-to-female sex reversal. It has been found that a variant in FGF9 gene may contribute to the occurrence of GD, and other gene variants can modulate the effects of this FGF9 mutation. These findings provide important insights into the etiology of GD.
Review
Genetics & Heredity
Aileen A. Nava, Valerie A. Arboleda
Summary: The OMICs cascade describes the hierarchical flow of information through biological systems. The epigenome sits at the apex of the cascade, regulating gene expression and cellular function. Mutations in epigenes can lead to developmental disorders, and the study of chromatinopathies using OMICs approaches provides valuable insight into disease pathogenesis and potential therapeutic targets.
Article
Medical Laboratory Technology
Laila M. Sathe, Nishrat N. Khan, Jazmine M. Williams, Rosita Saul, Kane Jajieh, Maryam R. Sartippour, Rachel Young, Joanna Xie, Dawn M. Marquette, Tiffany Duncan, Eleazar Eskin, Valerie A. Arboleda
Summary: The use of the SwabSeq diagnostic platform for massive-scale SARS-CoV-2 testing presented challenges in quality assurance due to the novelty and scale of sequencing-based testing. To address mapping errors, we implemented quality control measures by placing negative controls alongside patient samples. We developed 2D paper templates for single racks and 3D printed plastic templates for multiple racks, significantly reducing plate mapping errors.
LABORATORY MEDICINE
(2023)
Review
Urology & Nephrology
Alejandra P. Reyes, Nayla Y. Leon, Emily R. Frost, Vincent R. Harley
Summary: In this review, the authors provide an overview of the embryology and genetics of typical sex development and discuss the clinical manifestations and genetic causes of differences in sex development. Sex development relies on gene networks and hormonal factors, and differences in sex development (DSD) can arise from congenital alterations during these processes. Understanding the genetics and embryology of sex development is essential for diagnosing and managing DSD, and advances have been made in understanding the genetic causes of DSD, especially for 46,XY DSD. Further research is needed to better understand 46,XX DSD and identify additional genetic causes.
NATURE REVIEWS UROLOGY
(2023)
Article
Medicine, Research & Experimental
Isabella Lin, Angela Wei, Zain Awamleh, Meghna Singh, Aileen Ning, Analeyla Herrera, Bianca E. Russell, Rosanna Weksberg, Valerie A. Arboleda, REACH Biobank and Registry
Summary: ASXL1 mutations in Bohring-Opitz syndrome disrupt multiple layers of the epigenome, activating Wnt signaling and affecting gene transcription. This multiomics approach provides insights into the pathogenesis of Bohring-Opitz syndrome and potential therapeutic targets for Myeloid leukemias.
Article
Endocrinology & Metabolism
Anthony D. Bird, Emily R. Frost, Stefan Bagheri-Fam, Brittany M. Croft, Janelle M. Ryan, Liang Zhao, Peter Koopman, Vincent R. Harley
Summary: During sex determination in mice, FGFR2c is involved in testis development while FOXL2 and WNT4/RSPO1 pathways drive ovarian development. The role of FGFR2 in the ovary and its requirement in the testis after sex determination are not clear.
Article
Genetics & Heredity
Sarah J. Spendlove, Leroy Bondhus, Gentian Lluri, Jae Hoon Sul, Valerie A. Arboleda
Summary: Congenital heart disease (CHD) is a rare structural defect, and common genetic variants have a modest but significant contribution to the phenotypic expression of CHD.
HUMAN GENETICS AND GENOMICS ADVANCES
(2022)
Article
Immunology
Evann E. Hilt, James Boocock, Marisol Trejo, Catherine Q. Le, Longhua Guo, Yi Zhang, Laila Sathe, Valerie A. Arboleda, Yi Yin, Joshua S. Bloom, Pin-Chieh Wang, Joann G. Elmore, Leonid Kruglyak, Lasata Shrestha, Shah A. Mohamed Bakhash, Michelle Lin, Hong Xie, Meei-Li Huang, Pavitra Roychoudhury, Alexander Greninger, Sukantha Chandrasekaran, Shangxin Yang, Omai B. Garner
Summary: This study found evidence of the early community spread of SARS-CoV-2 in the Los Angeles area, well before widespread diagnostic testing was being conducted in early 2020. The virus was introduced into the area from both domestic and international sources as early as January.
CLINICAL INFECTIOUS DISEASES
(2022)