UCLA geneticists identify cause of malformed genitalia, finding will improve sex assignments in ambiguous newborns

UCLA researchers have determined that a second copy of a human sex gene can convert an embryo from male to female, often resulting in ambiguous genitalia. Reported in the May edition of the American Journal of Human Genetics, the findings offer new hope for parents whose babies are born with this condition - as well as valuable information to help physicians more accurately and quickly diagnose the newborn's gender.

"Genital malformations are an unspoken yet frequent public health problem," said Dr. Eric Vilain, UCLA assistant professor of human genetics and principal investigator of the study. "Parents don't speak of it because they fear others will consider their children taboo or shameful."

"Our discovery offers insight into the genetic pathway of sex determination - what makes a man male and a woman female," added Vilain, a pediatrician who counsels parents whose children are born with genital malformations.

Mild cases of malformed genitalia - such as undescended testes or an enlarged clitoris - occur in one percent of all births, affecting 3 million people and their families. More severe cases - in which infants are born with such sexually ambiguous genitals that obstetricians cannot inform the parents whether they had a boy or girl - occur in one out of 3,000 births.

Vilain and his team pinpointed WNT-4, a signaling gene on chromosome 1, as one of a handful of known genes responsible for human sex determination. Unlike classic genetic defects that result from the absence or mutation of a gene, genital malformations occur when WNT-4 appears twice on the chromosome.

"These findings suggest that WNT-4 influences the sex determination pathway at each step of the way," Vilain said. "We discovered that when the amount of the gene fluctuates even slightly at any stage in the genetic blueprint, it changes the embryo from male to female."

The UCLA team's findings will enable physicians to use molecular testing to identify the genetic causes of sexually ambiguous genitalia in newborns. In turn, this tool will improve diagnosis for sex assignment.

"WNT-4 offers another diagnostic clue that explains why certain cases of sexual development go awry," Vilain said. "Firm diagnosis through genetic testing will equip physicians with the information they need to help parents make important medical choices early in their child's life."

Vilain's laboratory next plans to explore whether scientists can reduce the chromosomal dose of WNT-4 in the embryo of pregnant women whose first child possessed malformed or ambiguous genitalia.

"Our findings suggest that clinicians could identify the WNT-4 duplication prenatally," Vilain said. "If this proves true, in the future we may be able to correct the defect in the womb and restore the embryo to its original male status. This may repair the genital malformations before the child is born."