Greenarray Genomics Newsletter : Your Genetic Blueprint to Better Health

Discovery of a Novel MVK Gene Variant in a Consanguineous Couple with Recurrent Pregnancy Loss

What if a single gene could explain the heartbreak of recurrent pregnancy loss?

In a recent case study, a consanguineous couple discovered they both carry a novel mutation in the MVK gene, offering a crucial clue to their tragic obstetric history. This finding not only sheds light on the genetic roots of their miscarriages but also paves the way for informed decisions about future pregnancies.

Case Presentation:

The couple presented with a significant obstetric history, having experienced five recurrent miscarriages, all before the eighth month of gestation. Clinical findings during these pregnancies included:

• Polyhydramnios: Excessive amniotic fluid surrounding the fetus.
• Fetal Ascites: Accumulation of fluid in the fetal abdomen.
• Recurrent Infections: Frequent infections during pregnancy.
• Fetal Hydrops: Severe edema (swelling) in the fetus.
• Bilateral Hypoplastic Lungs: Underdeveloped lungs.
• Fetal Hepatomegaly: Enlarged fetal liver.
• Fetal Tachycardia: Abnormally rapid heart rate in the fetus.

Could a single gene be the key to understanding their losses?

Despite these clinical indicators, karyotyping analyses of the couple revealed normal results (46XY for the male and 46XX 21 psi+ for the female), providing no clues to the cause of their recurrent losses.With no significant results from standard tests, the couple decided to undergo exome testing, which examines all of the protein-coding genes in a genome.

Genetic Analysis and Findings

The exome test uncovered that both partners were carriers of a mutation in the MVK gene, responsible for producing the enzyme mevalonate kinase. This enzyme plays a crucial role in the non-sterol isoprenoid biosynthesis pathway. Mutations in this gene lead to Mevalonate Kinase Deficiency (MKD), a metabolic auto-inflammatory syndrome.

The MVK Gene and Its Role:

The MVK gene is located on chromosome 12 (12q24). Mevalonate kinase, the enzyme it encodes, plays a crucial role in the mevalonate pathway, which is vital for the biosynthesis of isoprenoids. Isoprenoids are necessary for multiple cellular functions, including:

• Cholesterol Biosynthesis: A precursor for cell membrane formation.
• Prenylation of Proteins: Essential for protein membrane attachment and function.
• Steroid Production: Important for various physiological processes.

Did you know there are two phenotypes of MKD?

1. Mevalonic Aciduria: Characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, recurrent febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash.
2. Hyperimmunoglobulinemia D Syndrome: Known for periodic fever and inflammatory symptoms similar to those seen in mevalonic aciduria.

The Novel MVK Variant:

?The novel variant detected in this couple has not been previously reported as pathogenic in association with mevalonic aciduria conditions. Hence, it is classified as a variant of uncertain significance (VUS). However, given the significant correlation between the couple's clinical pregnancy findings and MKD symptoms, it is suspected that this MVK gene mutation is responsible for the observed fetal conditions leading to pregnancy loss.

Why is this discovery significant?

This autosomal recessive condition means that if both parents are carriers of the same MVK gene mutation, there is a high likelihood their offspring would be affected by mevalonic aciduria. This discovery has provided the couple with crucial information, enabling them to make informed decisions about future pregnancies.

Implications for Future Conceptions:

?As MKD is an autosomal recessive condition, there is a 25% chance that each of their offspring will be affected by the disorder if both parents are carriers. The identification of the MVK mutation allows the couple to make informed decisions regarding their reproductive options, such as:

• Preimplantation Genetic Diagnosis (PGD): A technique used in conjunction with in vitro fertilization (IVF) to screen embryos for genetic conditions before implantation.
• Prenatal Testing: Options include chorionic villus sampling (CVS) or amniocentesis to test for MKD in the fetus during early pregnancy.
• Genetic Counseling: Professional counseling can help the couple understand the risks, implications, and available options for future pregnancies.

This case underscores the importance of genetic testing in diagnosing unexplained recurrent pregnancy loss. The detection of a novel MVK gene variant in this couple provides crucial information that can guide their reproductive choices and offers hope for achieving a successful pregnancy. Advances in genetic analysis continue to play a pivotal role in unraveling the complexities of genetic contributions to reproductive health.

Uncovering a novel MVK gene variant in a couple with a history of recurrent pregnancy loss highlights the power of genetic testing. It opens doors to new understandings and possibilities in managing and preventing such heart-wrenching experiences. As genetics continues to evolve, so does the hope for countless couples seeking answers to their reproductive challenges.

What's next for genetic research in obstetrics? Stay tuned!