The clinical picture of STAG2 germinative variants varies with the nature of the mutation: loss-of-function variants, missense variants and gene duplications: (1) Loss-of-function variants consist of a multisystem disorder that may include holoprosencephaly, affect primarily heterozygous females and are believed to be lethal in males with a 46,XY karyotype (Mullegama et al. (2017)).
(2) Missense mutations have been reported twice: in a family with six affected males connected through healthy females (Soardi et al. (2017)) and one isolated case with an unaffected mother (Mullegama et al. (2019)).
(3) Gene duplications have been found as part of the so-called Xq25 duplication. In these cases, the main clinical manifestations are intellectual deficiency and facial hypotonia (Phillippe et al. (2013); Yingjun et al. (2015); Leroy et al. (2016)).
It is believed that the clinical manifestations of STAG2 germinative mutations are more connected to the role of STAG2 in gene regulation than properly in the mechanical cohesin role.
Diagnostic testing can be done by whole exome sequencing (WES), including CNV analysis.
STAG2