The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Department of Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, China.
Liver Int. 2022 Feb;42(2):402-411. doi: 10.1111/liv.15104. Epub 2021 Nov 29.
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.
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.
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).
The phenotype of MYO5B deficiency was associated with MYO5B genotypes, the nullity or the domain affected.
MYO5B 的双等位致病性变异可导致微绒毛包涵病（MVID）或家族性肝内胆汁淤积症（FIC）。报道的 FIC 患者数量较少，因此基因型-表型相关性尚未完全阐明。本研究旨在报告更多 MYO5B 相关 FIC 患者，并更详细地将基因型与表型相关联。
总结了 12 例新诊断的 MYO5B 相关（包括 11 例 FIC）患者的表型和遗传数据，以及 118 例已有基因型的先前报道患者。仅招募具有双等位 MYO5B 变异的患者。无义、移码、经典剪接位点、起始密码子缺失以及单个外显子或多个外显子缺失被定义为 MYO5B 无效变异。
表型上，50 例为孤立性 MVID，47 例涉及肝脏和肠道（联合），33 例为孤立性 FIC（9 例持续性、15 例复发性、3 例短暂性和 6 例未分类）患者。肠道表现的严重程度与无效变异数量的增加呈正相关（ρ=0.299，P=0.001）。所有 FIC 患者均携带至少一个非无效变异，且胆汁淤积的严重程度与无效变异的存在相关（ρ=0.420，P=0.029）。携带影响 MYO5B 非运动区的错义/框移变异的 FIC 患者比例（16/29，55%）明显高于 MVID（3/25，12%，P=0.001）和联合患者（3/31，10%，P=0.000）。在 29 例 FIC 患者中，有 10 例在 IQ 基序中携带错义/框移变异，而在 56 例 MVID 和联合患者中则没有（P=0.000）。
MYO5B 缺乏症的表型与 MYO5B 基因型、无效性或受影响的结构域有关。
