Research Explained: Prenatal Diagnosis of Okur-Chung Syndrome: Ultrasound Findings and Implications of CSNK2A1 and KCNQ5 Variants

Kratochwila et al.

Research Explained by: Lindsay Bass, CSNK2A1 Foundation Intern

Edited by: Gabrielle Rushing, PhD, CSNK2A1 Foundation Chief Scientific Officer

Reviewed by Parent Advisory Board members: Michelle Proctor-Simms and Miranda Finn

Okur-Chung Neurodevelopmental Syndrome (OCNDS) is a rare disease caused by heterozygous mutations in the CSNK2A1 gene. This means that only one copy of the altered gene is required for OCNDS to occur. OCNDS is typically characterized by neurodevelopmental delay, distinct facial characteristics, and speech and language issues. Mutations in a different gene, KCNQ5 (which regulates neuron function), were identified in patients with severe epilepsy leading to cognitive impairment.

A report by Kratochwila et al. described a 37-year-old pregnant South American woman with a non-related partner. The woman regularly consumed cannabis and tobacco throughout her pregnancy. She had a history of voluntary pregnancy terminations and uncomplicated deliveries. The first trimester was uneventful, and prenatal screening showed a lower risk for various chromosomal abnormalities. However, at 21(+3) weeks, an anatomy scan showed cerebellar hypoplasia (an under-developed cerebellum) and other brain malformations, as well as fetal growth impairment. At 23(+4) weeks, a detailed ultrasound revealed further brain abnormalities, including the presence of a Blake’s pouch cyst (which normally resolves with fetal development) and vermis rotation (turning of the central part of the cerebellum). Facial abnormalities were also observed, including a short nasal bone. 

A genomic hybridization array showed no chromosomal abnormalities. However, whole exome sequencing, which analyzes all exons (the protein coding regions) in the human genome, identified novel de novo (new and not inherited) mutations in CSNK2A1 and KCNQ5. CSNK2A1 had a probable pathogenic substitution (missense variant) c.118C>G (p.Gln40Glu), affecting a conserved loop structure of the protein. KCNQ5 had a heterozygous nonsense mutation (p.Ser429Argfs*8), classified as pathogenic. A multidisciplinary clinical team advised the parents of the poor prognosis due to the fetal brain abnormalities and genetic findings. The couple chose to terminate the pregnancy at ~26 weeks. Sequencing of the parents’ DNA did not detect either of these mutations; therefore, risk of recurrence in future pregnancies is low but not zero. Further studies are needed to confirm whether the fetal brain malformations observed here were due to mutations in CSNK2A1, KCNQ5, or both genes. This is the first report of a CSNK2A1 mutation detected before birth.