Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females

Abstract

Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama–Klein–Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. Conclusions: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders.

Whole Exome-Trio Analysis Reveals Rare Variants Associated with Congenital Pouch Colon

“…Congenital Pouch Colon (CPC) is a rare type of high anorectal malformation wherein a part of or the entire colon becomes dilated in the form of a pouch with a fistula connecting genitor-urinary tract [15]. Most have been reported in India with cases common to other countries accounted for, although males are prone to be largely affected, with a male to female ratio of 4:1 [16].…”

“…Most have been reported in India with cases common to other countries accounted for, although males are prone to be largely affected, with a male to female ratio of 4:1 [16]. The incidence of CPC is highest in north-west regions of India, and is estimated to be 5-18% of the total number of neonates managed for anorectal malformations [15]. From WES approaches, we have earlier identified mutations that are associated with CPC and reported candidate missense mutations [17].…”