Identification of a Novel <i>FOXP1</i> Variant in a Patient with Hypotonia, Intellectual Disability, and Severe Speech Impairment

The FOXP subfamily includes four different transcription factors: FOXP1, FOXP2, FOXP3, and FOXP4, all with important roles in regulating gene expression from early development through adulthood. Haploinsufficiency of FOXP1, due to deleterious variants (point mutations, copy number variants) disrupting the gene, leads to an emerging disorder known as “FOXP1 syndrome”, mainly characterized by intellectual disability, language impairment, dysmorphic features, and multiple congenital abnormalities with or without autistic features in some affected individuals (MIM 613670). Here we describe a 10-year-old female patient, born to unrelated parents, showing hypotonia, intellectual disability, and severe language delay. Targeted resequencing analysis allowed us to identify a heterozygous de novo FOXP1 variant c.1030C>T, p.(Gln344Ter) classified as likely pathogenetic according to the American College of Medical Genetics and Genomics guidelines. To the best of our knowledge, our patient is the first to date to report carrying this stop mutation, which is, for this reason, useful for broadening the molecular spectrum of FOXP1 clinically relevant variants. In addition, our results highlight the utility of next-generation sequencing in establishing an etiological basis for heterogeneous conditions such as neurodevelopmental disorders and providing additional insight into the phenotypic features of FOXP1-related syndrome

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C&gt;T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families