VP16.05: Prenatal diagnosis of Zellweger syndrome using clinical-exome sequencing

Abstract

Zellweger syndrome (ZS; OMIM #214100) is a fatal autosomal recessive disorder of peroxisome biogenesis and is characterized by muscular hypotonia, facial dysmorphism, renal cysts, hepatomegaly, severe psychomotor retardation, and failure to thrive.

In this report, we present a case of Zellweger syndrome with associated prenatal ultrasound softmarkers and clinical exome sequencing confirmation.

A healthy 30-years-old G2P1 with previous uneventful pregnancy was referred to our center at 31 gestational weeks because of suspected abnormalities on prenatal ultrasound. First trimester screening had shown low risk combined test with NT of 1mm. There was no consanguinity or any other relevant past history.

Ultrasound at 23 gestational weeks at a local healthcare center revealed rhizomelia and mild bilateral ventriculomegaly. Amniocentesis was performed but found no abnormality by chromosomal microarray analysis.

At 31 gestational weeks, a level 3 ultrasound examination in our center showed mild right sided ventriculomegaly, square shape of bilateral frontal horns, subependymal cysts, thin but morphologically normal corpus callosum, Blake’s pouch cyst with abnormal bullet shape of 4th ventricle, hepatospleenomegaly and rhizomelia with stippled epiphyses. Additionally, magnetic resonance imaging scan revealed polymicrogyria in frontal lobes and right Sylvius fissure. The patient opted for clinical exome sequencing to screen for genetic causes. Clinical exome sequencing found homozygous point-nonsense mutation (NM_000318:c.373C>T (p.Arg123Ter)) in PEX2 gene. The peroxisomal biogenesis disorder Zellweger syndrome with mutations in PEX2 gene was consistent with clinical diagnosis of this fetus. Counseling about the prognosis of ZS was provided to the parents and termination was opted by both parents.

Detection of mild ventriculomegaly and rhizomelia on second trimester ultrasound should be indicative for clinical exome sequencing to rule out ZS and associated genetic conditions. Because of its fatality in early life, prenatal diagnosis and genetic counseling for ZS are crucial for planning care in future pregnancies.