Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia.
Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Genes (Basel). 2024 Jul 19;15(7):946. doi: 10.3390/genes15070946.
An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS).
Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected.
Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy.
This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.
使用联合全基因组测序（WGS）研究两种不相关的肌肉营养不良和普拉德-威利综合征（PWS）（OMIM#176270）遗传疾病的共发生情况。
对一名患有 PWS、长时间肌肉张力减退伴高肌酸激酶血症和早发性肥胖的先证者进行三体系列 WGS 联合分析，以调查其遗传病因。父母均未受影响。
结果显示，先证者的 15 号染色体存在母源单亲二体性（UPD），从 15q11.2 扩展到 15q22.2，包括 15q11.2-15q13 区域的 PWS 区域。15q22.2 到 15q26.3 检测到母源杂合性。在母亲中以杂合状态鉴定出 15q15.1 上的致病性变异 NM_000070.3(CAPN3):c.550del (p.Thr184fs)，该变异在先证者中因母源单亲二体性而呈纯合状态，在先证者中呈纯合状态。
这是首例在同一位患者中同时研究 PWS 和钙蛋白酶病（OMIM#253600）的分子病因的研究。本报告强调了联合分析的实用性，以及在具有复杂和不明原因表型的患者中评估常染色体隐性疾病时需要考虑单亲二体性区域的必要性。
