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. 2024 Jul-Sep;20(3):277-285.
doi: 10.4183/aeb.2024.277. Epub 2025 May 23.

A NEW-FOUND ARMC5 GERMLINE VARIANT IN PRIMARY BILATERAL MACRONODULAR ADRENAL HYPERPLASIA USING WHOLE-EXOME SEQUENCING AND PROTEIN PREDICTIVE ANALYSIS

Y Zhang  1   2 , Y Tao  1   3 , Q Wu  1   3 , X Liu  1   3 , C Zou  1   3 , H Geng  1   3
Affiliations

A NEW-FOUND ARMC5 GERMLINE VARIANT IN PRIMARY BILATERAL MACRONODULAR ADRENAL HYPERPLASIA USING WHOLE-EXOME SEQUENCING AND PROTEIN PREDICTIVE ANALYSIS

Y Zhang et al. Acta Endocrinol (Buchar). 2024 Jul-Sep.

Abstract

Objective: ARMC5 mutations are responsible for the development of primary bilateral macronodular adrenal hyperplasia (PBMAH). In this study, we aimed to report a novel ARMC5 germline variant in a PBMAH patient family.

Method: CT examination and dexamethasone suppression test (DST) were used in the diagnosis of PBMAH. Sanger sequencing was used to validate the familial heredity. For the novel variant, protein predictive analysis was performed to study the changes of secondary and tertiary structures and hydrophobicity.

Results: A 45 years old male (proband, III-1) was diagnosed as PBMAH. Whole-exome sequencing (WES) was performed, finding one mutation: c.719_ 724dup, p Arg240_ Pro241dup. Sanger sequencing showed the II-2, III-1, IV-1 with heterozygous gene, confirming the familial heredity. For protein predictive analysis, the predicted secondary structure of variants has one alpha-helix structure incomplete compared with normal ARMC5. The tertiary structure could draw the same conclusion, that hydrophobicity decreases after mutation.

Conclusion: We reported a new-found ARMC5 germline variant in PBMAH using WES and protein predictive analysis. With the help of WES, early diagnosis of PBMAH could help variant carriers to prevent the occurrence of cancer by lifetime follow-up.

Keywords: ARMC5; PBMAH; WES; germline variant; protein predictive analysis.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
The pedigree of the family. According to the genetic testing, III-1 is the proband and patient. II-2 and IV-1 is the carrier; II-1 and IV-2 have no gene mutation.
Figure 2
Figure 2
Imaging examination of the proband (III-1). (a) In 2016, enlargement of bilateral adrenal glands was considered as proliferation. (b) In 2022, enlargement of bilateral adrenal glands was considered as proliferation. (c) In 2023, enlargement of bilateral adrenal hyperplasia combines with multiple nodules and masses.
Figure 3
Figure 3
ARMC5 germline variant in the peripheral blood of part of the family number. Sanger sequencing confirmation for the candidate causative variant of ARMC5 in the peripheral blood sample of the family members.
Figure 4
Figure 4
Predicted secondary structures of ARMC5 variants. Figure 4 consists of three stripes, with above one the wild type of ARMC5, below one the variant and middle one their differences. Differences are highlighted in red rectangle, of which black stripes mean no difference, orange and red ones mean significant difference. In protein sequence 231-251, mutation in ARMC5 make the alpha spiral incomplete.
Figure 5
Figure 5
Predicted tertiary structures of ARMC5 variants. The picture above is wild type of ARMC5, and the picture below is ARMC5 variant. The difference is shown in the red circle.
Figure 6
Figure 6
Hydrophobicity of tertiary structures of ARMC5 variants. In the tertiary structures, blue means hydrophilic amino acids, white means neutral amino acids, yellow means hydrophobic amino acids. The difference is shown in the red circle. After mutation, hydrophobicity decreases.
See this image and copyright information in PMC

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