A step closer to discovering the causes of growth disorder

Hudson Institute researchers have identified new genetic factors that could help to uncover the causes of the rare overgrowth disorder, Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann Syndrome (BWS) is a growth disorder that predisposes children to a greater risk for developing certain types of cancer, including Wilms Tumour (a paediatric kidney cancer).

Infants affected by this disorder are considerably larger than normal and continue to grow and gain weight at an unusual rate during childhood until around eight years of age. The syndrome has several different genetic causes, resulting in varying symptoms.

A new study, led by Associate Professor Elizabeth Algar, with PhD student Vinod Dagar, recently published in Clinical Epigenetics, examined 55 children with a common sub-type of BWS. They uncovered key changes in a gene called DNMT1.

“We identified rare genetic changes in DNMT1 in three cases of BWS, which is key to the folate pathway and a major enzyme responsible for maintaining methylation at imprinted genes in the developing embryo,” A/Prof Algar said.

“We were able to show these genetic changes could have contributed to the abnormal genomic methylation in a subgroup of children with BWS.”

Mutations in several other genetic factors that affect the methylation of imprinted genes in the developing embryo have been recently uncovered by scientists.

“This work adds to the understanding of the factors that regulate genomic imprinting, a process that ensures the correct dosage of specific parental genes in the developing embryo,” A/Prof Algar said.

“Our findings could help to define the genetic and environmental causes of BWS, and paves the way for larger global studies which could lead to a test for genetic causes of BWS in affected families.”

What is Beckwith-Wiedemann Syndrome?

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition that affects approximately 1 in 10,000 people worldwide.

Signs and symptoms may include

• Large birth weight, and children are larger than normal, usually until age eight, when growth slows down, resulting in an average height in adults.
• Opening in the wall of the abdomen that allows the abdominal organs to protrude through the belly-button.
• Umbilical hernia (soft out-pouching around the belly-button).
• Abnormally large tongue which may interfere with breathing, swallowing and speaking.
• Abnormally large abdominal organs.
• Creases or pits in the skin near the ears.
• Low blood sugar (hypoglycemia) in infancy.
• Kidney abnormalities.

Children with BWS are at an increased risk of developing several types of cancerous and noncancerous tumors, particularly a rare form of kidney cancer called Wilms tumour, a cancer of muscle tissue called rhabdomyosarcoma and a form of liver cancer called hepatoblastoma. Tumours develop in about 10 percent of people with this condition and almost always appear in childhood. Older children and adults are much less likely to have serious medical problems associated with the condition.

What is DNA methylation?
DNA methylation is the main way gene activity is adjusted during life, especially during early development.
It is an epigenetic mechanism used by cells to control gene expression. A number of mechanisms exist to control gene expression, but DNA methylation is a commonly used epigenetic signalling tool that can fix genes in the “off” position.
Scientists have made various discoveries over recent decades about DNA methylation and how vital it is to a number of cellular processes such as embryonic development, X-chromosome inactivation, genomic imprinting, gene suppression, carcinogenesis and chromosome stability. Researchers have linked abnormal DNA methylation to several adverse outcomes, including human diseases.

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