Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.

What's Already Known About This Topic? Aneuploidy screening using cell‐free DNA has recently been expanded to include selected microdeletion syndromes. However, real‐world performance characteristics for the majority of these variants remain unknown. Many primary obstetric providers are unaware of performance limitations and appropriate clinical contexts for ordering these assays. What Does This Study Add? Cell‐free DNA screening using a commercial platform designed to detect chromosomal microdeletions can lead to false negative results, even in the case of a pregnancy at known high risk because of a previous child with 4p‐ syndrome and a paternal translocation carrier. This finding underscores the need for clinician education about the limitations of such testing, the utility of invasive diagnostic testing in similar high‐risk pregnancies, and additional validation of cell‐free DNA assays for microdeletions before further expansion into routine practice.