Perrault syndrome (PRLTS) is an autosomal recessive disease with sensorineural hearing loss and ovarian dysfunction in girls, and either a fluctuating neurological phenotype or not. PRLTS type 2 is known to be caused by pathogenic variants of the CLPP gene that encodes mitochondrial ATP-dependent protease. This paper involved clinical and genetic studies on a Pakistani family with PRLTS. Whole-exome sequencing identified a novel homozygous CLPP missense mutation (NM_006012.4: c.250 A > C; p.Ile84Leu). Its pathogenicity was assessed with the help of multiple sequence alignment, AlphaFold protein modeling, and docking with CLPX with the help of ClusPro. Auditory brainstem responses and tympanometry were in clinical assessment. The individuals were found to have a uniform phenotype of severe sensorineural hearing loss, mild intellectual disability, ataxia and frequent fever. There was one patient in whom the unilateral Eustachian tube dysfunction was hinted at by Tympanometry. At the molecular level, the identified CLPP variant involved a highly conserved residue. Structural modeling showed preserved protein architecture, whereas docking simulations revealed disrupted CLPP-CLPX interaction, suggesting a basis for impaired proteostasis. We report a novel CLPP missense variant (p.I84L) in a Pakistani family with PRLTS, expanding the mutational spectrum of CLPP. To the best of our knowledge, recurrent fever was reported in PRLTS for the first time, which expanded the PRLTS phenotype spectrum.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and primary ovarian insufficiency (POI) secondary to ovarian dysgenesis. However, the mutation spectrum of disease-causing genes for Perrault syndrome in the Chinese population remains poorly understood. In this study, we report on two Chinese families with Perrault syndrome type 3 caused by novel CLPP gene variants. We also conducted a comprehensive literature review of CLPP gene variants in Perrault syndrome type 3 to elucidate genotype-phenotype associations. Using Whole Genome Sequencing (WGS) data, two pedigrees with Perrault syndrome type 3 were ascertained in the Chinese Deafness Genetics Cohort through genotype-driven analysis. Variants were validated using Sanger sequencing and copy number quantification methods. In vitro analysis of splice site variants in the CLPP gene using the minigene assay. Two Han Chinese families were ascertained: one with compound heterozygous variants (c.270 + 1G > C and c.355A > C [p. Ile119Leu]) and the other with missense variant (c.400G > C [p. Asp134His]) together with a large deletion in CLPP. In vitro minigene assays confirmed that the c.270 + 1G > C variant causes intron 2 retention and an alternative 5' splice site in exon 2, leading to protein alteration. Among 33 Perrault syndrome type 3 patients in literature, 97% (31/32) had hearing loss, 55% (16/29) neurological disease, and 71% (15/21) females had POI. Including our 4 novel variants, 21 pathogenic CLPP gene variants have been reported, with 57% (12/21) missense and 43% (9/21) truncating variants, mainly in the ATP-dependent Clp protease proteolytic subunit. Biallelic truncating or missense plus truncating genotypes showed higher rates of neurological disease (p = 0.001), but no significant difference in hearing loss incidence compared to biallelic missense genotypes was observed. This study highlights the challenges in diagnosing Perrault syndrome due to its genetically and clinically heterogeneity. By exploring novel variants and establishing genotype-phenotype correlations, we aim to improve the genetic diagnosis and consultation for this complex disorder. The purpose of this overview is to: 1.. Briefly describe the clinical characteristics of Perrault syndrome; 2.. Review the genetic causes of Perrault syndrome; 3.. Review the differential diagnosis of Perrault syndrome with a focus on genetic conditions; 4.. Provide an evaluation strategy to identify the genetic cause of Perrault syndrome in a proband (when possible); 5.. Review management of Perrault syndrome; 6.. Inform genetic counseling of family members of an individual with Perrault syndrome.

A female, term neonate, born via vaginal delivery to a G5P1D1A3 hypothyroid mother with a history of an elder sibling being homozygous for HSD17B4 mutation, diagnosed while working up his progressive neurological disorder and succumbing to the same. The family screening revealed that both parents were heterozygous carriers of the same mutation in the gene HSD17B4 After genetic counselling, amniocentesis revealed the fetus to be having homozygosity for the same mutation. In view of precious pregnancy, normal antenatal scans and investigations, the pregnancy was continued, and baby was born with a birth weight of 2.65 kg and had a smooth perinatal transition. Parents were counselled regarding the course of the illness, possible complications and the need for regular follow-up. Ultrasound of the abdomen, pelvis and head was normal in the neonatal period. She was vaccinated as per the national schedule and gaining weight normally.

Syndromic hearing loss (SHL) is characterized by hearing impairment accompanied by other clinical manifestations, reaching over 400 syndromes. Early and accurate diagnosis is essential to understand the progression of hearing loss and associated systemic complications. In this study, we investigated the genetic etiology of sensorineural hearing loss in three Moroccan patients using whole exome sequencing (WES). The results revealed in two families Perrault syndrome caused by LARS2, p. Asn153His; p. Thr629Met compound heterozygous variants in two siblings in one family; and p. Thr522Asn, a homozygous variant in two sisters in another. The patient in the third family was diagnosed with D-bifunctional protein deficiency (D-BPD), linked to compound heterozygous mutations p. Asn457Tyr and p. Val643Argfs*5 in HSD17B4. Molecular dynamic simulation results showed that Val643Argfs*5 does not prevent HSD17B4 protein from binding to the PEX5 receptor, but further studies are recommended to verify its effect on HSD17B4 protein functionality. These results highlight the effectiveness of WES in identifying pathogenic mutations involved in heterogeneous disorders and the usefulness of bioinformatics in predicting their effects on protein structure.

Objective: To investigate the molecular etiology of Perrault syndrome by analyzing the clinical phenotype and pathogenic gene variants of 2 male patients with bilateral severe sensorineural deafness. Methods: Two male patients with Perrault syndrome characterized by severe sensonrineual deafness adimitted to the First Affiliated Hospital of Zhengzhou University between February 2021 and March 2022 were selected, and the clinical phenotype and pathogenic gene variants of them and their family members were summarized. The whole exome sequencing technology was used to screen the pathogenic variants of the probands, and the candidate variants were determined by combining with clinical phenotype. The probands and their family members were verified by the Sanger sequencing method. Results: The whole exome sequencing results showed that the proband of family 1 had a compound heterozygous variants of the LARS2 (NM_015340.4) gene c.1565C>A (p.Thr522Asn) and c.1079T>C (p.Ile360Thr). The reported pathogenic variant c.1565C>A came from the mother, and the novel variant c.1079T>C came from the father. The second proband harbored compound heterozygous variants of HARS2 gene (NM_012208.4) c.1273C>T (p.Arg425Trp) and c.1403G>C (p.Gly468Ala), with the former from the proband's mother, the latter from the father. The c.1273C>T was novel and c.1403G>C was the reported pathogenic variant. All above variants were respectively classified as pathogenic, uncertain significance, uncertain significance and likely pathogenic based on the ACMG guidelines. Conclusion: This study expands the mutational spectrum of LARS2 and HARS2 genes, which highlights that genetic testing plays an important role in the early diagnosis of syndromic deafness. 目的： 分析并揭示Perrault综合征患者的分子病因。 方法： 选取郑州大学第一附属医院2021年2月至2022年3月收治的2例以双耳重度感音神经性听力损失为特征的男性Perrault综合征患者，总结患者及其家系的临床表型及基因变异，应用全外显子测序（whole exome sequencing，WES）技术对先证者进行致病变异筛选，结合临床表型确定候选基因及致病位点，用Sanger测序法对先证者及其家系成员进行验证。 结果： WES结果显示家系1的先证者存在LARS2基因（NM_015340.4）c.1565C>A（p.Thr522Asn）和c.1079T>C（p.Ile360Thr）的复合杂合变异，c.1565C>A来自先证者母亲，c.1079T>C来自先证者父亲。其中，c.1565C>A为已报道的致病变异，c.1079T>C为新变异。家系2先证者携带HARS2基因（NM_012208.4）c.1273C>T（p.Arg425Trp）和c.1403G>C（p.Gly468Ala）的复合杂合变异，c.1273C>T来自母亲，c.1403G>C来自父亲，c.1273C>T为新变异，c.1403G>C为已报道可能致病变异。参考美国医学遗传学与基因组学学会基因变异分类标准，上述变异分别评级为致病、意义未明、意义未明和可能致病。 结论： 本研究扩大了LARS2和HARS2基因的突变谱，基因检测在综合征型耳聋的早期诊断中发挥着重要作用。.