NSMCE2 / MMS21 structural variant causes chromosome breakage syndrome with primordial dwarfism and severe lung disease

Abstract Primordial dwarfism (PD) is a genetic disorder characterized by severe intrauterine and postnatal growth failure. While some subtypes involve impaired DNA damage responses, the molecular basis of PD remains incompletely defined. We describe two siblings of non-consanguineous Indian-Jewish ancestry with a likely autosomal recessive syndrome featuring borderline intrauterine growth restriction, severe postnatal growth restriction, hypotonia, consistent dysmorphic features (elongated face, low-set ears, hypotelorism, prominent nose), hypothyroidism, late-onset insulin-dependent diabetes, borderline immune dysregulation, and recurrent pneumonia with interstitial lung disease, leading to death in adolescence. Karyotype and microarrays were normal, but cytogenetic analysis of PHA-stimulated lymphocytes revealed spontaneous chromosomal breakage and polyploidy, without hypersensitivity to cross-linking agents. Linkage analysis, whole genome sequencing, and Manta structural variant calling identified a homozygous tandem duplication within NSMCE2 , NC_000008.11(NM_173685.4:c.265-11431_418+8879dup), validated by PCR and Sanger sequencing. RT-PCR of lymphoblastoid cells confirmed an aberrant transcript, predicted to cause a frameshift, premature stop codon, and loss of the SUMO domain. NSMCE2 encodes a core component of the SMC5/6 complex, essential for chromosome structure and repair. Only one prior report has linked NSMCE2 mutations to PD. Our findings determine the clinical and molecular spectrum of this severe chromosome breakage syndrome with PD, lung fibrosis, immune-endocrine abnormalities, and early lethality.