We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-β signaling pathway exhibit arterial aneurysms and dissections as key features.

Objective: To report atypical MRI patterns associated with POLR3A and POLR3B mutations.Methods: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.Results: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants.Conclusion: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders.Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders. POLR3-related leukodystrophy is a rare autosomal recessive disease characterized by hypomyelination often accompanied by dental abnormalities and hypogonadotropic hypogonadism. [1][2][3][4][5] In its classical form, the association of these features is referred to as 4H syndrome.1,2 Mutations in the POLR3A and POLR3B genes, which encode for the 2 largest subunits of the RNA polymerase III (POLR3) complex, as well as in POLR1C, also encoding a POLR3 subunit, are responsible for this disease. [6][7][8][9][10][11] With the identification of the causative genes, patients with suggestive clinical or MRI picture can undergo genetic testing, confirming the diagnosis. 12 The MRI pattern of POLR3-related leukodystrophy is suggestive and characterized by diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.12-14 Recognition of this pattern was proven effective in detecting patients with 4H leukodystrophy caused by POLR3A-B or POLR1C mutations and is therefore *These authors contributed equally to this work. ‡Dual last authors.