Perrault syndrome: Clinical report and retrospective analysis

Abstract

Background: Perrault syndrome (PRLTS4; OMIM# 615300) is a rare autosomal recessive disorder and only a few cases have been reported worldwide. We report a Chinese female characterized by sensorineural hearing loss and premature ovarian insufficiency.

Methods: We evaluated audiological, endocrine, and ultrasound examinations and examined the genetic causes using whole-exome sequencing. We reviewed the literature to discuss the pathogenesis, genotype-phenotype correlation, treatment, and prevention of PRLTS4.

Results: Bioinformatic analysis revealed compound heterozygous mutations in the LARS2 gene, c.880G>A (p.Glu294Lys), and c.2108T>C (p.Ile703Thr) which is a novel missense mutation, co-segregated in this family. Taken together, the patient was clinically diagnosed as PRLTS4. The literature review showed that the phenotype for PRLTS4 varies widely, but the sensorineural hearing loss, increased gonadotropin levels, and amenorrhea occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there is a mutation hotspot for PRLTS4.

Conclusion: This study expanded the mutation spectrum of LARS2 and is the first report of PRLTS4 in a Chinese family. Genetic testing plays an important role in early diagnosis of syndromic deafness and clinical genetic evaluation is essential to guide prevention.

Keywords: LARS2; Perrault syndrome; premature ovarian insufficiency; sensorineural hearing loss.

Figure 1

Pedigree, Sanger sequencing, and Audiograms of the PRLTS4 family. (a) Pedigree of the PRLTS4 family. (b) Sanger sequencing of the proband (Ⅱ‐1), parents (Ⅰ‐1, Ⅰ‐2), and younger brother (Ⅱ‐2). (c) Early audiograms of the proband. (d) Present audiograms of the proband

Figure 2

Amino acid conservation analysis of mutations reported in the literatures (black box) and the novel mutation c.2108T>C (p.Ile703Thr) in this study (red box)

Figure 3

Structure of the wild‐type and mutant mtLeuRS. (a) Structure of the wild‐type residue p.Glu294. (b) Structure of the mutant residue p.Glu294. In the p.Glu294Lys mutation, the Glu‐to‐Lys substitution replaces the carboxyl group with an amine group. (c) Structure of the wild‐type residue p.Ile703. (d) Structure of the mutant residue p.Ile703. The p.Ile703Thr mutation induces the increase of two hydrogen bonds, altering the interaction of residues p.Ile703, p.Thr699, p.Thr700, and p.Ala707

Figure 4

LARS2 mutation spectra of PRLTS4 and domain architecture of LARS2