We present a case of LGMD2 with a previously unreported variant in JAG2.

Limb-girdle muscular dystrophy recessive 27 (LGMD2) is linked to biallelic variants in the JAG2 gene, which encodes the Notch ligand Jagged2. The Notch signaling pathway plays a critical role in the development and maintenance of various tissues, including skeletal muscle. While 27 affected individuals from multiple families have been documented, we present a case of LGMD2 with a previously unreported variant in JAG2, detailing the clinical, radiological, and histopathological findings.

We report a 16-year-old woman with a two-year history of slowly progressive weakness predominantly affecting her lower limbs. She experienced difficulty standing from a seated position and climbing stairs, without any facial weakness, contractures, or spinal abnormalities. Her parents are first-degree cousins, and she has an older sister with similar but milder symptoms. Physical examination revealed muscle power of 2/5 in hip flexion and 4/5 in knee flexion, with other muscle groups normal. Deep tendon reflexes were symmetric and intact, and sensory examination showed no deficits. Laboratory tests indicated elevated creatine kinase (359 U/L), while nerve conduction studies were unremarkable. Electromyography demonstrated nonirritable myopathic changes in proximal muscles. MRI of the pelvis and thighs revealed severe atrophy and fatty infiltration, with a left thigh muscle biopsy showing focal myopathic changes, including fatty replacement, endomysial fibrosis, and smaller type |myofibers. Whole exome sequencing identified a homozygous JAG2 variant (c.2203C>T; p.Arg735Cys), classified as a variant of unknown significance by ACMG guidelines.

The clinical, radiological, and histopathological features associated with the identified JAG2 variant are vital for accurate diagnosis and risk assessment in affected families.