A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenicLMNA missense variants, associated with unaltered expression levels of lamins Aand C, without accumulation of wild-type or deleted prelamin A isoforms, as observed inHutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNAmissense variant, (p.Thr528Met), was previously identified in a compound heterozygousstate in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygositywas recently identified in patients affected by Type 2 familial partial lipodystrophy.Here, we report four unrelated boys harboring homozygosity for thep.Thr528Met, variant who presented with strikingly homogeneous APS clinical features,including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescenceanalyses of patient-derived primary fibroblasts showed a high percentage ofdysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of laminB1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggestingpathophysiology-associated clues. These four cases further confirm that a specificLMNA variant can lead to the development of strikingly homogeneous clinical phenotypes,in these particular cases a premature aging phenotype with major musculoskeletalinvolvement linked to the homozygous p.Thr528Met variant