Genetic evaluation

Identifying a Variation of Sex Characteristics (VSC)/Difference of Sex Development (DSD) requires, first of all, an evaluation of the karyotype (a test that can assess the number and structure of a person's chromosomes) to determine which sex chromosomes are present in the cells of the person being examined. Based on the clinical suspicion, targeted genetic testing can then be carried out to identify the genetic characteristics underlying the specific VSC/DSD. The percentage of cases in which the genetic cause can be identified varies greatly among groups; for example, it is very high for 46,XX subjects with congenital adrenal hyperplasia, while it is around 50% in 46,XY subjects with VSCs/DSDs.

Why should you do a genetic evaluation of a VSC/DSD?
It can be useful to:

• identify the VSC/DSD
• foresee the evolution of the VSC/DSD. For example, knowing what kind of hormone production will occur in adolescence can simplify any therapeutic choices to be made in childhood
• calculate the risk of recurrence of the VSC/DSD in the family. By identifying the genetic alteration and studying its hereditary mode of transmission, estimates can be made about the likelihood of recurrence in the family

For VSCs/DSDs with an autosomal recessive mode of transmission, such as congenital adrenal hyperplasia or 5-α-reductase deficiency, in almost all cases both parents carry a mutation and the probability of having a child with a VSC/DSD is 25%. In contrast, for X-chromosome-related VSCs/DSDs, such as androgen insensitivity syndrome, if the mother carries the mutation, there is a 50% probability of having a 46,XY child with a VSC/DSD. However, more often than not the mother is not a carrier and the mutation originates de novo (i.e., is the result of a novel event) so the risk of recurrence is almost zero.

How is a genetic evaluation carried out?
Genetic testing is prescribed by a medical specialist (e.g., geneticist, endocrinologist, gynecologist), and can usually be performed under health care expense exemption for suspected rare disease. Once the genetic mutation has been identified in the person with a VSC/DSD, the evaluation can be extended to family members.

The testing is often preceded by genetic counselling to explain its purpose, limitations, and characteristics to the intersex person and/or their parents.

Various biological materials can be used for genetic analysis: blood, saliva, chorionic villus (part of the placenta), amniotic fluid (the fluid that surrounds the fetus during pregnancy), etc.

If the clinician or the geneticist suspect a VSC/DSD, further research will determine possible causes:

• numerical or structural chromosomal variation using cytogenetic or cytogenomic techniques: karyotype, SNP-array, CGH-array
• gene mutations using molecular biology techniques: sequencing, Multiple Ligation-dependent Probe Amplification, MLPA

Laboratory results will be sent to the physician who requested them, who will in turn contact the person or the person's family, in case of a minor, to inform about the results.

When is it possible to get a genetic evaluation?
It is possible to have a genetic evaluation made at any time from prenatal life to adulthood. Prenatal testing can be performed both in the case of clinical suspicion of a VSC/DSD in the fetus (for example, due to incongruence between chromosomal sex and the sex seen on ultrasound) or to look for a specific variation if a VSC/DSD is recurrent in the family.

Bibliography
Audi L et al.  The EU COST Action. GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’. European Journal of Endocrinology. 2018 Oct 1;179(4):R197-R206
Baetens D et al. Update on the genetics of differences of sex development (DSD). [Absract]. Best Practice & Research. Clinical Endocrinology & Metabolism. 2019 Jun;33(3):101271