A female case of L1 syndrome that may have developed due to skewed X inactivation.

BACKGROUND: Heterozygous L1CAM variants cause L1 syndrome with hydrocephalus and aplasia/hypoplasia of the corpus callosum. L1 syndrome usually has an X-linked recessive inheritance pattern; however, we report a rare case occurring in a female child.

CASE PRESENTATION: The patient's family history was unremarkable. Fetal ultrasonography revealed enlarged bilateral ventricles of the brain and hypoplasia of the corpus callosum. The patient was born at 38 weeks and 4 days of gestation. Brain MRI performed on the 8th day of life revealed enlargement of the brain ventricles, marked in the lateral and third ventricles with irregular margins, and hypoplasia of the corpus callosum. Exome sequencing at the age of 2 years and 3 months revealed a de novo heterozygous L1CAM variant (NM_000425.5: c.2934_2935delp. (His978Glnfs * 25). X-chromosome inactivation using the human androgen receptor assay revealed that the pattern of X-chromosome inactivation in the patients was highly skewed (96.6 %). The patient is now 4 years and 11 months old and has a mild developmental delay (developmental quotient, 56) without significant progression of hydrocephalus.

CONCLUSION: In this case, we hypothesized that the dominant expression of the variant allele arising from skewed X inactivation likely caused L1 syndrome. Symptomatic female carriers may challenge the current policies of prenatal and preimplantation diagnoses.