Whole-exome sequencing revealed a novel mutation of the ALMS1 gene in a Chinese family with Alström syndrome: a case report

Abstract

Background: Alström syndrome (AS) is a rare autosomal recessive disorder that leads to multiple organ fibrosis and failure. Precise diagnosis from the clinical symptoms is challenging due to its highly variabilities and its frequent confusion with other ciliopathies and genetic diseases. Currently, mutations in the ALMS1 gene have been reported as a major cause of AS, thus, it is crucial to focus on the detection and discovery of ALMS1 mutations.

Case presentation: We present a case of a 13-year-old Chinese boy weighing 70 kg and standing 168 cm tall. He has two younger brothers. Their parents hail from different ancestral homes in eastern and northern China. The patient's primary clinical findings included visual impairment at the age of four and progressive hearing loss starting at the age of ten. Subsequently, at the age of twelve, the patient developed hyperlipidaemia and hyperinsulinemia. Ultrasonographic findings indicated the presence of gallstones and mild fatty liver. His Body Mass Index (BMI) significantly increased to 25 kg/m² (ref: 18.5-23.9 kg/m²). Additionally, echocardiography revealed mild mitral and tricuspid regurgitation. Ultimately, Whole Exome Sequencing (WES) identified a new missense mutation in the ALMS1 gene (NG_011690.1 (NM_015120): c.9536G > A (p.R3179Q)). This missense mutation generated an aberrant splicer and disrupted the stability and hydrophobicity of proteins, which preliminarily determined as " likely pathogenic". Therefore, considering all the above symptoms and molecular analysis, we deduced that the patient was diagnosed with AS according to the guidelines. We recommended that he continue wearing glasses and undergo an annual physical examination.

Conclusion: In this case report, we report a novel homozygous ALMS1 mutation associated with AS in the Chinese population, which expands the mutation spectrum of ALMS1. Genetic testing indeed should be incorporated into the diagnosis of syndromic deafness, as it can help avoid misdiagnoses of AS. While there is no specific treatment for AS, early diagnosis and intervention can alleviate the progression of some symptoms and improve patients' quality of life.

Keywords: ALMS1; Alström syndrome; Mutation; Whole exome sequencing.

Fig. 1

Videonystagmography results

Fig. 2

Visual examination. A Optical Coherence Tomography (OCT) of the proband showing thinning and irregular arrangement of retinal pigmentation. The left figure displays the results from 2017, while the right figure presents the results from 2021. B Visual field examination revealed visual field defects in both eyes. C Results of the Electroretinogram (ERG)

Fig. 3

Ultrasonic examination and echocardiography. A Results of ultrasound examinations. The two images at the top are from 2021, and the three images at the bottom are from 2022. B Development of scoliosis and epiphysis. C Presence of acanthosis nigricans. D Echocardiography findings

Fig. 4

Molecular detection. A The pedigree of this family. The proband (II-1), parents (I-1, I-2), and two brothers (II-2, II-3), along with the sequencing results of the ALMS1 family. B Position of the amino acid mutation. C The abscissa represents the sequence position, and the ordinate represents the amino acid scale value. The scale is defined by the high scoring value of hydrophobic amino acids: > 0 indicates hydrophobicity, and < 0 indicates hydrophilicity. The negative value predicted from the graph combined with gravy suggests that the protein produced by mutation sites is hydrophilic. D The closer the score is to 1, the greater the potential damage. The results are categorized into beneficial, probably damaging, and possibly damaging