Titel: NSDHL mutation as a rare cause of fetal cortical malformation
ID: P-ClinG-065
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Alrun Hotz (Freiburg/DE)

Abstract - Text


Introduction: Pathogenic variants in genes related to the migration and differentiation of cortical neurons can result in malformations of cortical development. Although whole exome sequencing analysis has been successfully implemented in prenatal diagnostics, in a substantial number of pregnancies with abnormal brain development the underlying cause remains unknown. Even with trio-based exome sequencing a large proportion of the identified variants remain of uncertain significance and further functional analyses are often limited or not performed in the prenatal setting.

Clinical report: We report on the prenatal findings of a 31-year-old healthy mother in her first pregnancy with a male fetus. Prenatal ultrasound at 18+6 weeks of gestation detected mild ventriculomegaly with suspicion of abnormal Insula and Cavum septi pellucidi. As fetal brain development can only be diagnosed later in the second trimester a control scan at 22+6 weeks confirmed suspicion of lissencephaly type 1 with abnormal gyration and absent corpus callosum. No other organ involvement was found but amniocentesis was performed. Due to the progressive cerebral maldevelopment the pregnancy was terminated and a fetal cord blood sample was obtained.

Methods and Results: Prenatal genetic diagnosis showed a normal male karyotype and no pathogenic deletion/duplication. Trio-based exome sequencing revealed the maternal hemizygous variant of unknown significance c.686+5G>A in the NSDHL gene on the X chromosome. Segregation analysis in the maternal family suggested a de novo mutation in the mother and X chromosome inactivation showed a skewed pattern. Further mRNA analysis of fetal cord blood demonstrated an aberrant splicing in the fetus: in at least 50% of the transcripts skipping of exon 6 of the NSDHL gene could be confirmed.

Conclusion: The NSDHL gene encodes 3β-hydroxysteroid dehydrogenase involved in cholesterol biosynthesis. Pathogenic variants can cause CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects, MIM #308050) and CK syndrome (MIM #300831). CHILD syndrome is an X-linked dominant disorder caused by variants which result in the loss of function of the NSDHL protein and usually is lethal in males. CK syndrome is an allelic X-linked recessive disorder with less than 20 patients reported so far. In our case the functional analysis of the fetal sample supports the pathogenicity of the NSDHL variant and makes the diagnosis of CK syndrome the most probable cause of the cortical malformation. As there seems to be an apparent preferential transmission to the offspring the recurrence risk in future male pregnancies is high. Our case describes for the first time prenatal ultrasound findings of CK syndrome and adds to the phenotypic spectrum of NSDHL disorders. It underlines the importance of trio-based WES in prenatal genetic diagnosis enabling proper genetic counseling and information on reproductive decisions and options to families.