Novel ITGA6 gene mutation ID’d in fetus with JEB: Case study

New disease-causing mutation linked to problems in digestive system

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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A pregnant woman cradles her belly with one hand while holding a teddy bear in the other.

A new mutation in the ITGA6 gene, called “a novel lethal variant” by researchers, was identified as the cause of junctional epidermolysis bullosa (JEB) that led to the death of a fetus at 32 weeks of pregnancy, according to a case reported in Saudi Arabia.

This was the third pregnancy for the parents, who are related, and were recommended genetic counseling should they seek to have future children.

In the described case, JEB was associated with pyloric atresia — a complete obstruction of the pylorus, the muscular opening that connects the stomach to the small intestine — and incomplete formation of the skin.

Given that such cases have a poor prognosis, researchers here recommended a “highly specialized technique,” known as preimplantation genetic diagnosis, or PGD, which involves testing an early embryo after in vitro fertilization to allow the uterine implantation of healthy embryos. The procedure is “revolutionary in the management of these cases,” the team noted, while also recommending testing for genetic mutations before birth in any future pregnancies.

The case was reported in “Epidermolysis Bullosa With Pyloric Stenosis: A Novel Lethal Variant,” published in the journal Cureus.

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Pregnancy was third for related parents

A moderate to severe type of epidermolysis bullosa, JEB is marked by blistering over large areas of the body. Like other forms of EB, it is caused by genetic mutations that disrupt the production of proteins required for holding the skin layers together.

JEB is inherited in an autosomal recessive pattern, meaning that both copies of the disease-causing gene, one inherited from each parent, are defective.

In this report, a research team from the International Medical Center Hospital, in Jeddah, described the case of a 33-year-old woman who was treated for suspected fetal death at 32 weeks of pregnancy, or about eight months along. She had no significant medical history, but she and her partner had consanguinity, which is most commonly defined as marriage between relatives who are second cousins or closer.

Her previous history included two pregnancies. The first was characterized by early fetal growth restriction in the uterus, a blockage of the small intestine, and a heart defect. The baby was born at 34 weeks by cesarean section, with fluid-filled (bullous) eruptions and peeling of the skin. The infant died two days after birth.

In the following year, her second pregnancy ended with fetal death at 32 weeks.

In her third pregnancy, she was followed at another hospital. Although her ultrasound normal, she was told at week 30 of pregnancy that she had excessive amniotic fluid.

A further ultrasound to confirm fetal death showed the fetus had a severely dilated stomach, indicating pyloric atresia. That scan also confirmed an excessive amount of amniotic fluid and a dilated ureter — tubes that transport urine from the kidneys to the bladder.

After birth, the fetus showed blistering of the skin and  a rare defect known as aplasia cutis congenital (ACC), which is characterized by the absence of skin tissue. The fetus also had low-set ears and nose malformations.

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Both parents found to be carriers of ITGA6 gene mutation

The couple was informed of the possibility of genetic abnormalities and offered genetic testing, which was done using a skin biopsy of the fetus. That testing revealed that the fetus carried two copies of an ITGA6 mutation — c.1688dup — one in each copy of the gene, which had never before been reported. The mutation was consistent with autosomal recessive epidermolysis bullosa with pyloric atresia, the team noted.

The couple received genetic counseling and was offered PGD for any future pregnancies.

“Although the variant of ITGA6 … has been labeled as likely pathogenic [disease-causing] by the laboratory due to a lack of other reports in the past, in our case, the three recurrent pregnancy losses most likely stemmed from this variant, as the parents were carriers of this autosomal recessive disorder,” the researchers wrote.

As carriers of this ITGA6 gene mutation, neither parent shows symptoms of the disease, but either one can pass on the mutation to any offspring. When both parents are carriers, there is a 25% chance of their child developing the disease.

Although the variant of ITGA6 … has been labeled as likely pathogenic [disease-causing] by the laboratory due to a lack of other reports in the past, in our case, the three recurrent pregnancy losses most likely stemmed from this variant, as the parents were carriers of this autosomal recessive disorder.

Mutations in the ITGA6 and ITGB4 genes change the expression of the alpha6B4 integrin, a protein important to maintaining the connection between the epidermis, or the skin’s top layer, with the dermis, which is the layer below the epidermis. These variant result in skin blistering, and in malformations in the digestive and urinary systems.

“The literature shows that JEB-[pyloric atresia]-ACC is most often lethal and suggests that ACC is a poor prognostic factor for JEB-PA patients,” the researchers wrote, adding, “As a result of skin barrier breakdown, these patients develop septicemia [a life-threatening complication from infection] … the most common cause of neonatal death in these cases.”

“Identification of the underlying genetic abnormality is critical for providing appropriate genetic counseling, prenatal testing, or PGD,” the team wrote.

Such techniques often play a crucial role in the management of affected families, the investigators noted, especially given the recurrence risk in any pregnancy with an autosomal recessive condition such as JEB.