Gene · 2024
Identification of novel compound heterozygous variants of the ALMS1 gene in a child with Alström syndrome by whole genome sequencing.
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Xu Haikun, Wang Ziju, Sa Sha, Yang Ying, Zhang Xiaofei, Li Dejun
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.