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Background   LAMA2 -related muscular dystrophy including  LAMA2 -related congenital muscular dystrophy ( LAMA2 -CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by  LAMA2  pathogenic variants. We aimed to describe the natural history and establish genotype–phenotype correlations in a large cohort of Chinese patients with  LAMA2 -related muscular dystrophy.    Methods  Clinical and genetic data of  LAMA2 -related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed.    Results  One hundred and thirty patients (116  LAMA2 -CMD and 14 LGMDR23) were included.  LAMA2 -CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of  LAMA2 -CMD patients at median ages of 6.0 months (range 2.0–36.0 months), 11.0 months (range 6.0–36.0 months), and 27.0 months (range 18.0–84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0–20.0 months). Motor regression in  LAMA2 -CMD mainly occurred concurrently with rapid progression of contractures during 6–9 years old. Twenty-four  LAMA2 -related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of  LAMA2 -CMD patients. Forty-six novel and 97 known  LAMA2  disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In  LAMA2 -CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in  LAMA2 -CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in  LAMA2 -CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival ( p  = 0.029).    Conclusions  This study provides better understandings of natural history and genotype–phenotype correlations in  LAMA2 -related muscular dystrophy, and supports therapeutic targets for future researches.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13023-021-01950-x.

Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort