NONO-Related Syndromic X-Linked Developmental Disability 34: Further Clinical and Molecular Delineation in a Prenatal Cohort.

objectiveTo characterize the prenatal sonographic features across different trimesters and genomic spectrum of NONO-related X-linked intellectual developmental disorder.

methodWe analyzed two fetuses presenting with corpus callosum agenesis and rare cardiac anomalies using genome sequencing and exome sequencing. A systematic literature review was conducted to provide a comprehensive analysis of genotype-phenotype correlations.

resultsTwo novel cases were reported in this study: one with a de novo 61.7 kb deletion affecting both NONO and ITGB1BP2, and another with a de novo c.1093 C > T(p.Arg365Ter), a recurrent variant reported in the literature. A total of 23 cases with NONO defects and prenatal phenotypes were identified, encompassing 19 distinct variant types. Large deletions and splicing variants accounted for approximately 32% (6/19). Among all cases, 78% (18/23) exhibited typical or concurrent brain abnormalities, such as corpus callosum agenesis, cardiac defects including left ventricular noncompaction (LVNC), or short long bones in the second trimester. Notably, 4% (1/23) of cases were reported with isolated intrauterine growth restriction (IUGR), primarily identified in the third trimester.

conclusionGenome sequencing facilitates thorough identification of the genetic causes of NONO-related syndrome. The recurrent variant p.Arg365Ter has been reported to cause variable cardiac abnormalities in different patients, suggesting that other genetic or non-genetic factors may contribute to the cardiac manifestations in NONO-related syndromes.