Rare Compound Heterozygous Frameshift Mutations in ALMS1 Gene Identified Through Exome Sequencing in a Taiwanese Patient With Alström Syndrome.

Meng-Che Tsai,Hui-Wen Yu,Peng-Chieh Chen,Tsunglin Liu,Yen-Yin Chou,Yuan-Yow Chiou

doi:10.3389/fgene.2018.00110

Meng-Che Tsai, Hui-Wen Yu + Show 4 more

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https://doi.org/10.3389/fgene.2018.00110

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Abstract

Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs*10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs*6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients.

Highlights

Alström syndrome (AS; OMIM 203800) is a rare autosomal recessive disorder characterized by early-onset blindness due to cone-rod dystrophy, juvenile obesity followed by marked insulin resistance and type 2 diabetes mellitus, and progressive sensorineural hearing impairment that usually takes place within the first year of life (Marshall et al, 2007a)
Two pathological mutations in ALMS1 were identified: chr2:73786171delTA (c.10290_10291delTA) in exon (Figure 1A, upper panel) and chr2:73799829delAG (c.10823_10824delAG) in exon (Figure 1A, lower panel). These mutations were further confirmed by Sanger sequencing (Figure 1B) and the results showed that c.10290_10291delTA (p.Lys3431Serfs∗10) was maternally inherited and c.10823_10824delAG (p.Arg3609Alafs∗6) was paternally inherited
We described a Taiwanese patient presenting clinical features compatible with AS, except the absence of hearing impairment

Summary

Introduction

Alström syndrome (AS; OMIM 203800) is a rare autosomal recessive disorder characterized by early-onset blindness due to cone-rod dystrophy, juvenile obesity followed by marked insulin resistance and type 2 diabetes mellitus, and progressive sensorineural hearing impairment that usually takes place within the first year of life (Marshall et al, 2007a). A certain portion of AS patients presents liver, kidney, neurological, cardiac, and pulmonary diseases (Marshall et al, 2005). No disease specific treatment is as yet available, whereas early morbidity and mortality are expected in affected patients. The causative gene of AS has been recently ascribed to ALMS1, which harbors 23 exons and encodes a 461-kDa protein (ALMS1, centrosome and basal body associated protein) involved in ciliary functions (Hearn et al, 2002).

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