Identification of novel compound heterozygous variants of the ALMS1 gene in a child with Alström syndrome by whole genome sequencing.

• Alström syndrome is a rare inherited ciliopathy caused by mutations in ALMS1 gene. • Our report is the first description of an ALMS patient with a CTS structure. • Novel compound heterozygous variants were identified in the patient. • The exact breakpoint site of the large deletion was determined by breakpoint analysis. • The deletion maybe formed through the microhomology-mediated end joining mechanism. Alström syndrome (ALMS), a rare recessively inherited ciliopathy caused by mutations in ALMS1 , is characterized by retinal dystrophy, childhood obesity, sensorineural hearing loss, and type 2 diabetes mellitus. The majority of pathogenic variants in ALMS1 are nonsense and frameshift mutations, which would lead to premature protein truncation, whereas copy number variants are seldom reported. Herein, we present a 10-year-old Chinese girl with ALMS. The potential causative genetic variant was confirmed through whole genome sequencing, quantitative real-time PCR analysis, and Sanger sequencing. Additionally, breakpoint analysis was performed to determine the exact breakpoint site of the large deletion and elucidate its probable formation mechanism. The patient had a cor triatriatum sinister (CTS) structure. Genetic analysis identified novel compound heterozygous variants in the patient, consisting of a frameshift variant c.4414_4415delGT (p.V1472Nfs*26) in ALMS1 and a novel large deletion at chr2:73,612,355–73,626,339, which encompasses exon 1 of the ALMS1 gene. Moreover, breakpoint analysis revealed that the large deletion probably formed through the microhomology-mediated end joining (MMEJ) mechanism due to the 6-bp microhomologies (TCCTTC) observed at both ends of the breakpoints. In this study, novel compound heterozygous variants in the ALMS1 gene were identified in an ALMS patient with a CTS structure. The molecular confirmation of these variants expands the mutational spectrum of ALMS1 , while the manifestation of ALMS in the patient provides additional clinical insights into this syndrome. [ABSTRACT FROM AUTHOR]