Supplementary Material for: Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies

Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the <i>LMNA</i> gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in <i>LMNA</i> and <i>ZMPSTE24</i>, respectively. <i>ZMPSTE24</i> in addition to <i>ICMT </i>encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with <i>LMNA</i> mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes <i>LMNA, ZMPSTE24</i> and<i> ICMT</i> in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in <i>LMNA</i> in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In <i>ZMPSTE24</i> and <i>ICMT</i>, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.