Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

Variants of are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-11, Vol.21 (22), p.8554
Main Authors: Martínez de LaPiscina, Idoia, Mahmoud, Rana Aa, Sauter, Kay-Sara, Esteva, Isabel, Alonso, Milagros, Costa, Ines, Rial-Rodriguez, Jose Manuel, Rodríguez-Estévez, Amaia, Vela, Amaia, Castano, Luis, Flück, Christa E
Format: Article
Language:English
Subjects:
Adolescent
Amenorrhea
Child
Child, Preschool
Cryptorchidism
Diagnostic systems
Disorder of Sex Development, 46,XY - genetics
Disorder of Sex Development, 46,XY - pathology
DNA-Binding Proteins - genetics
Female
Females
Genes
Genetic Variation
Genotype & phenotype
Heredity
Heterozygote
Humans
Hypotheses
Infant
Infant, Newborn
Male
Multifactorial Inheritance
Patients
Phenotypes
Phosphoproteins - genetics
Protein expression
Proteins
Receptors, Peptide - genetics
Receptors, Transforming Growth Factor beta - genetics
Sex determination
Sex hormones
Steroidogenic Factor 1 - genetics
Testosterone
Transcription Factors - genetics
Uterus
Vagina
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Summary:Variants of are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the gene. We tested the transactivation activity of novel variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes , and in three individuals. Our study increases the number of variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous variation.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21228554