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Year : 2022  |  Volume : 25  |  Issue : 12  |  Page : 2077-2080

Identification of a novel mutation in ALMS1 in a Chinese patient with monogenic diabetic syndrome by whole-exome sequencing

Department of Endocrinology; Fujian Diabetes Research Institute; Metabolic Diseases Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Date of Submission13-Aug-2022
Date of Acceptance22-Sep-2022
Date of Web Publication19-Dec-2022

Correspondence Address:
Dr. Sun-Jie Yan
20 Chazhong Road, Taijiang District, Fuzhou - 350 005, Fujian
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_544_22

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Alstrom syndrome (AS) is one type of monogenic diabetic syndromes caused by mutation in the ALMS1. Due to rare prevalence and overlaps of clinical symptoms, monogenic diabetes is often misdiagnosed. Here, we report a Chinese diabetes patient with poor blood glucose control and insulin resistance. With whole-exome sequencing (WES), this patient was classified into monogenic diabetes and diagnosed as AS with one novel gene mutation identified. This study highlights the clinical application of WES in the diagnosis of monogenic diabetes.

Keywords: Alstrom syndrome, diabetes mellitus, monogenic diabetes, whole-exome sequencing

How to cite this article:
Zhong M, Huang LN, Zhang SJ, Yan SJ. Identification of a novel mutation in ALMS1 in a Chinese patient with monogenic diabetic syndrome by whole-exome sequencing. Niger J Clin Pract 2022;25:2077-80

How to cite this URL:
Zhong M, Huang LN, Zhang SJ, Yan SJ. Identification of a novel mutation in ALMS1 in a Chinese patient with monogenic diabetic syndrome by whole-exome sequencing. Niger J Clin Pract [serial online] 2022 [cited 2023 Feb 1];25:2077-80. Available from:

   Introduction Top

Diabetes mellitus is a metabolic disease and classification is needed after the diagnosis of diabetes for determining therapy.[1] There is one rare type called monogenic diabetes. It is caused by genetic mutations. Due to the clinical overlaps and complexity, monogenic diabetes is often misdiagnosed.[2],[3] Here, we report a clinical application of whole-exome sequencing (WES) in assisting the identification of Alstrom syndrome (AS).

   Case Report Top

A 30-year-old Han Chinese female with diabetes for over 20 years was admitted to this hospital because of poor glycemic control (glycosylated hemoglobin 13.0%). High-dose insulin therapy was needed (84 IU/day). Her height was 142 cm (<third centile), her weight 57 kg, and her waist-to-height ratio 0.62 with sparse hair [Figure 1]a. She has no polydactyly [Figure 1]b and [Figure 1]c.
Figure 1: Clinical features of the patient: (a) the hair of the patient, (b) normal fingers, and (c) normal toes

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On admission, the results of 0 and 2-hour oral glucose tolerance test about C-peptide were 2.72 nmol/L and 2.65 nmol/L. More than 20 years ago, her vision gradually decreased. Nystagmus and blindness occurred at the age of 12. Pattern visual-evoked potential indicated P100 wave amplitude of both eyes decreased, suggesting optic nerve damage. Flash electroretinography suggested abnormal cone-rod cells. She has evidence of renal failure secondary to diabetic nephropathy. One year before her most recent admission, her estimated GFR was 66.92 mL/min consistent with grade 2 renal failure. On admission, eGFR was 14.61 mL/min consistent with end-stage renal failure. Kidney biopsy revealed diabetic nodular glomerulosclerosis. Twenty years ago, she was diagnosed with chronic otitis media following which she developed sensorineural deafness for which she was prescribed hearing aids. Peripheral blood chromosome analysis was 46, XX karyotype. She had hypertension and hypertriglyceridemia for 6 years. Menstruation began at the age of 15 and was irregular. Her parents are not a related marriage. Her parents, grandmother, and her uncle were diagnosed with type 2 diabetes. This patient has a younger brother with normal glucose tolerance.

Gene test was done in Precisiongenes Technology, Inc. (Haimen, China). All sequencing was performed on the Nova seq 6000 platform (Illumina). Variants with minor allele frequency less than 0.05 in population databases and expected to occur in the coding/splicing region were selected.[4] Sanger sequencing was performed to confirm the mutation. The summary of sequencing parameters can be found in [Table 1].
Table 1: High-throughput sequencing parameters

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The patient had two nonsense pathological variants in exon 8 of ALMS1: c.3896C>A: p.Ser1299 * (chr2: 73677553) and c.6673C>T: p.Gln2225 * (chr2: 73680330) [Figure 2]a. The result was confirmed by Sanger sequencing [Figure 3]. The gene regions c.3896C>A and c.6673C>T involved are highly conserved in human [Figure 2]b. c.3896C>A is a rare variant, with a population frequency of 0.0001 in East Asian backgrounds according to VarCards. The population frequency of c.6673C>T is not found in VarCards. According to the guideline,[5] the two mutations are pathogenic. Sanger sequencing showed that her father was heterozygous for c.3896C>A mutation. Her mother was heterozygous for c.6673C>T mutation. The proband was a heterozygous complex mutation [Figure 3].
Figure 2: The mutations in exon and the affected structure in protein: (a) the alignment of sequences indicated two substitutions in exon 8 of ALMS1 and (b) amino acid sequence conservation analysis in human and some species

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Figure 3: The family pedigree and Sanger sequence analysis. Proband was indicated by a black arrow; mutation was indicated by a red arrow. Her father was heterozygous for c.3896C>A mutation and her mother was heterozygous for c.6673C>T mutation. The proband was heterozygous complex mutations

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Modification of lifestyle, diets, exercise, and follow-up were administered. Due to renal insufficiency, insulin was used to control blood glucose (68 IU/day). Liraglutide was performed to maintain her body weight. For other systemic complications, we treated symptomatically.

   Discussion Top

Diabetes with particular clinical manifestations needs to be considered monogenic diabetes. Compared to conventional genetic analysis, WES is more effective and efficient.[6] Here, we report a young diabetes patient with poor blood glucose control. With WES, the patient was diagnosed as AS.

The patient's diabetes history has been clear for more than 20 years. It could be easily misdiagnosed as common type of diabetes. However, features of young age onset diabetes, long duration but reserved islet function and insulin resistance, are different from type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes of adults. It was required to consider monogenic diabetes. The clinical manifestations of AS are extremely diverse.[3] In childhood, it is often characterized by cone-rod dystrophy, blindness, and neurosensorial deafness. Adolescents and adults often present with metabolic syndrome, progressive fibrosis, and sexual dysfunction.[7] Bardet–Biedl syndrome also needs to be ruled out though this patient did not present mental retardation or polydactyly (toe) deformity. We used WES to screen for possible mutations and found the patient had two mutations in the ALMS1 gene.

AS is an autosomal-recessive disease caused by mutations in the exons of ALMS1 gene. ALMS1 protein contains a tandem repeat sequence domain, leucine Zipper, serine-rich region, and an ALMS motif.[8] ALMS1 is widely expressed in tissues and is an intracellular protein related to cell cilia function. Most of mutations in ALMS1 related with AS are nonsense mutations or frameshift mutations. Nonsense mutations often result in premature termination codons and truncated proteins. The most common pathogenic mutations at the DNA level are substitution and at the protein-level frameshifts.[9] The most common type of mutation is compound heterozygous mutation, which is consistent with our patient.

This patient has two AS-related pathogenic mutations in ALMS1 including c.3896C>A and c.6673C>T. c.3896C>A had been reported previously[10] and c.6673C>T is a novel mutation. Mutation in c.3896C>A originated from her father; c.6673C>T mutation originated from her mother. The proband was a heterozygous complex mutation in ALMS1 gene. Two mutations are nonsense mutations and located at conserved regions, resulting in ALMS1 mRNA premature degradation or truncated protein occurred. Patients with exon 8 mutations usually have normal or mild abnormal renal function. Surprisingly, our patient has severe renal impairment, which may be due to her long course of the disease.

Patients and families should be followed up in a multidisciplinary center. For patients with diabetes and obesity, modification of lifestyle, exercise, and diet are recommended. In addition to insulin, insulin-sensitizing agents can also be used to control blood glucose. GLP-1 receptor agonists can be performed on obese patients. Corresponding treatment is also required if patients are complicated with other syndromes.[3],[8]

   Conclusion Top

We diagnosed a long-term diabetes patient as AS by WES and identified one novel ALMS1 gene pathogenic mutation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Author contributions

Ming Zhong contributed to the acquisition of data and wrote the manuscript; Sun-Jie Yan revised the manuscript critically for important intellectual content and conducted the design of the study; and Ling-Ning Huang and Song-Jing Zhang contributed to discussion and the data analysis.


The authors would like to thank the patient and her family. The authors also want to express their gratitude to Dr. Yi-Hua Yao from the Department of Ophthalmology, the First Affiliated Hospital of Fujian Medical University.

Financial support and sponsorship

This study was supported by Joint Funds for the Innovation of Science and Technology, Fujian province (grant number: 2020Y9114).

Conflicts of interest

There are no conflicts of interest.

   References Top

Malik A, Ananthakrishnan S: Diabetes Physical Examination. Med Clin North Am 2022;106:483-94.  Back to cited text no. 1
Baldacchino I, Pace NP, Vassallo J. Screening for monogenic diabetes in primary care. Prim Care Diabetes 2020;14:1-11. doi: 10.1016/j.pcd.2019.06.001.  Back to cited text no. 2
Choudhury AR, Munonye I, Sanu KP, Islam N, Gadaga C. A review of Alström syndrome: A rare monogenic ciliopathy. Intractable Rare Dis Res 2021;10:257-62.  Back to cited text no. 3
Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The Human Gene Mutation Database: Towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017;136:665-77.  Back to cited text no. 4
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-23.  Back to cited text no. 5
Hansen MC, Haferlach T, Nyvold CG. A decade with whole exome sequencing in haematology. Br J Haematol 2020;188:367-82.  Back to cited text no. 6
Hearn T. ALMS1 and Alström syndrome: A recessive form of metabolic, neurosensory and cardiac deficits. J Mol Med 2019;97:1-17. doi: 10.1007/s00109-018-1714-x.  Back to cited text no. 7
Dassie F, Favaretto F, Bettini S, Parolin M, Valenti M, Reschke F, et al. Alström syndrome: An ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity. Endocrine 2021;71:618-25.  Back to cited text no. 8
Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, et al. Monogenic diabetes syndromes: LocusRohayem Jams D, Hardy C, Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Hum Mutat 2017;38:764-77.  Back to cited text no. 9
Yang L, Li Z, Mei M, Fan X, Zhan G, Wang H, et al. Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alström syndrome. BMC Med Genet 2017;18:75.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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