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MYO5B-associated diseases: Novel liver-related variants and genotype-phenotype correlation
Li Wang1, Yi-Ling Qiu1, Hong-Mei Xu2
1The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Background & Aims:
Biallelic pathogenic variants in MYO5B cause microvillus inclusion disease (MVID), or familial intrahepatic cholestasis (FIC). The reported FIC patients are scarce and so the genotype-phenotype correlation has not been fully characterised. This study aimed to report more MYO5B-associated FIC patients and correlate genotypes to phenotypes in more detail.
Methods:
The phenotype and genetic data of 12 newly diagnosed MYO5B-associated (including 11 FIC) patients, as well as 118 previously reported patients with available genotypes, were summarised. Only patients with biallelic MYO5B variants were enrolled. Nonsense, frameshift, canonical splice sites, initiation codon loss, and single exon or multiexon deletion were defined as null MYO5B variants.
Results:
Phenotypically, 50 were isolated MVID, 47 involved both liver and intestine (combined), and 33 were isolated FIC (9 persistent, 15 recurrent, 3 transient, and 6 un-sub-classified) patients. The severity of intestinal manifestation was positively correlated to an increased number of null variants (ρ = 0.299, P = .001). All FIC patients carried at least one non-null variant, and the severity of cholestasis was correlated to the presence of a null variant (ρ = 0.420, P = .029). The proportion of FIC patients (16/29, 55%) harbouring missense/in-frame variants affecting the non-motor regions of MYO5B was significantly higher than that of MVID (3/25, 12%, P = .001) and combined patients (3/31, 10%, P = .000). 10 of the 29 FIC patients harboured missense/in-frame variants at the IQ motifs comparing to none in the 56 MVID and combined patients (P = .000).
Conclusions:
The phenotype of MYO5B deficiency was associated with MYO5B genotypes, the nullity or the domain affected.
Insights
Genetic variants in MYO5B cause microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC). This study links MYO5B genotypes to MVID and FIC phenotypes, revealing genotype-phenotype correlations.
Area of Science:
- Genetics
- Molecular Biology
- Pediatric Gastroenterology
Background:
- Biallelic pathogenic variants in the MYO5B gene are the known cause of microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC).
- Previous reports on FIC patients are limited, hindering a comprehensive understanding of genotype-phenotype correlations.
- This research expands the cohort of MYO5B-associated FIC patients to further characterize these relationships.
Purpose of the Study:
- To identify and analyze additional patients with MYO5B-associated FIC.
- To establish detailed genotype-phenotype correlations in MVID and FIC.
- To investigate the impact of specific MYO5B variant types and locations on disease presentation.
Main Methods:
- Collected phenotype and genetic data from 12 newly diagnosed and 118 previously reported patients with biallelic MYO5B variants.
- Classified variants as 'null' (nonsense, frameshift, splice site, etc.) or non-null.
- Analyzed correlations between variant types, affected gene regions, and clinical phenotypes (MVID, FIC, combined liver-intestine involvement).
Main Results:
- Disease phenotypes included isolated MVID (50), combined liver-intestine (47), and isolated FIC (33).
- Increased null variants correlated with more severe intestinal manifestations (ρ=0.299, P=0.001).
- FIC patients with at least one non-null variant showed cholestasis severity correlated with null variant presence (ρ=0.420, P=0.029).
- FIC patients (55%) were more likely to have missense/in-frame variants in non-motor regions compared to MVID/combined patients (10-12%, P<0.001).
- Notably, 10 FIC patients had variants in IQ motifs, absent in MVID/combined groups (P=0.000).
Conclusions:
- The clinical presentation of MYO5B deficiency is significantly influenced by the specific genotype.
- The type of MYO5B variant (null vs. non-null) and the affected protein domain are critical determinants of MVID and FIC phenotypes.
- Genotype-phenotype correlations provide a more detailed understanding of MYO5B-related disorders.
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