2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A Novel Heterozygous Frameshift Variant in ITIH5 Associated with Type II Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

A Novel Heterozygous Frameshift Variant in ITIH5 Associated with Type II Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome
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In this case report, the authors describe a 15-year-old female with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type II, which is characterized by the absence of the uterus and certain parts of the vagina, along with extragenital anomalies like renal agenesis and prolactinoma. The patient had primary amenorrhea and underwent various imaging and laboratory tests. Genetic analysis revealed a heterozygous frameshift variant in the ITIH5 gene. ITIH5 encodes a protein involved in the extracellular matrix dynamics of the Müllerian structures. Prior cases have shown that ITIH5 loss-of-function can play a role in the pathogenesis of MRKH Type II. MRKH syndrome is a genetically heterogeneous disorder that affects the development of the Müllerian and Wölffian duct structures. There are over 40 candidate genes associated with MRKH, and ITIH5 deletion has been previously reported. The patient's family history did not reveal any similar conditions, and physical examination showed normal external genitalia development for age and sex. Cytogenetic analysis and chromosomal microarray analysis did not detect any significant copy number changes or abnormalities. Genetic testing using a custom next-generation sequencing panel identified the frameshift variant in ITIH5. This variant is predicted to truncate the protein, leading to the replacement of the last 130 amino acids with 60 different amino acids. The frequency of this variant in large population cohorts is 0.0011%. Overall, this case provides further evidence supporting ITIH5 as a candidate gene for MRKH syndrome, particularly in cases with extragenital anomalies.

Asset Subtitle

Presenting Author - Michael A. Finkel, DO, MPH; Co-Author - Vinod K. Misra, MD, PhD, FAAP, FACMG;

Meta Tag

Clinical History

Congenital Anomaly

Delineation of Diseases

Etiology

Exome sequencing

Genetic Testing

Genotype-Phenotype Correlations

Identification of Disease Genes

NextGen Sequencing

Phenotype

Co-Author Vinod K. Misra, MD, PhD, FAAP, FACMG

Presenting Author Michael A. Finkel, DO, MPH

Keywords

Mayer-Rokitansky-Küster-Hauser syndrome

MRKH syndrome type II

absence of uterus

absence of vagina

renal agenesis

prolactinoma

primary amenorrhea

ITIH5 gene

extracellular matrix dynamics

Müllerian structures