Clinical manifestations of Armfield syndrome in females with heterozygous FAM50A variants and skewed X-chromosome inactivation.

backgroundThe FAM50A gene encodes the FAM50A protein, which has been reported to be a putative spliceosomal C-complex protein and has also been implicated in several types of cancer. Pathogenic FAM50A variants have been associated with an X-linked recessive disorder known as Intellectual developmental disorder, X-linked syndromic, Armfield type (MRXSA).

methodsWe report the case of a Spanish female patient with macrocephaly, global developmental delay, and leukoencephalopathy. Whole-exome sequencing (WES) was performed to investigate the underlying genetic cause of the patient's condition. RNA expression analyses were subsequently carried out to assess the pathogenicity of the novel FAM50A variant.

resultsWES identified a novel heterozygous de novo FAM50A variant in the patient (NM_004699.4:c.905 A > T, p.His302Leu). The c.905 A > T variant was preferentially expressed from the paternal allele as a result of skewed X-chromosome inactivation (XCI). To further support our findings, we searched for additional individuals through the international data-sharing platform GeneMatcher and identified another unrelated female with MRXSA carrying a different novel heterozygous FAM50A variant (c.866G > A, p.Arg289Gln).

conclusionsIn conclusion, we report, for the first time, the clinical manifestations of MRXSA in two females carrying heterozygous FAM50A variants. In one patient, we further identify skewed XCI as a potential pathogenic mechanism and describe leukoencephalopathy as a previously unrecognized phenotypic feature. Together, these findings expand the genetic and, potentially, the neuroradiological spectrum associated with FAM50A variants.