Homozygous novel truncating variant of CLPP associated with severe Perrault syndrome

A female proband and her affected niece are homozygous for a novel frameshift variant of CLPP. The proband was diagnosed with severe Perrault syndrome encompassing hearing loss, primary ovarian insufficiency, abnormal brain white matter and developmental delay. Recessive variants of CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, PRORP, RMND1, and TWNK are associated with Perrault syndrome (PRLTS), a rare multisystem disorder.1, 2 PRLTS is characterized by mild to profound bilateral sensorineural hearing loss (SNHL) in females and males. Females may exhibit ovarian dysgenesis, characterized by complete or partial loss of gonadal development resulting in POI, presenting as primary amenorrhea and delayed puberty, or menopause before the fourth decade of life.1, 2 Some affected individuals have neurological impairment, including epilepsy and developmental delay, often associated with brain white matter changes.3 Here, we describe a novel homozygous variant NM_006012.4:c.383_399dup, p.(Asp134Argfs*49) of CLPP segregating in a consanguineous Pakistani family, ascertained with written informed consent after IRB approval from the University of the Punjab (FWA00017939) and from Combined NIH IRB (OH93DC0016). The p.(Asp134Argfs*49) is predicted to result in premature translation termination, and was identified from exome sequence of the proband (IV:4) and her affected 4 year-old niece (Figure 1A). There were no convincing pathological biallelic variants in the other eight PRTLS-associated genes. CLPP is transcribed ubiquitously (ENSG00000125656 GTEx) and partners with CLPX forming an ATP-dependent proteolytic chamber in mitochondria. The 15 yo proband (IV:4) of family PKDF2079 has congenital, bilateral, profound SNHL, a learning deficit, absent pubic hair and breast development, and brain white matter changes. Her hormonal profile measured on two different days is consistent with hypergonadotropic hypogonadism, with low serum estradiol concentration (<11.8 pg/mL; postmenopausal range for age, <21; 14–19 year <255), high follicle-stimulating hormone (FSH) level (110.27 mIU/mL; postmenopausal range, 19.3–100.6 mIU/mL; Tanner stage 1: 0.6–4.1) and high luteinizing hormone (LH) level (23.59 mIU/mL; postmenopausal range, 14.2–52.3 mIU/mL; Tanner stage 1: <0.1). She has not started hormonal replacement. Transabdominal pelvic ultrasound shows a hypoplastic uterus (3.3 × 1.1 cm) and a streak right ovary (5 × 7 mm) without follicles. Her left ovary is not visualized, overall, a profile consistent with POI. No other variants in our exome data explain either the hearing loss or the ovarian dysfunction. The p.(Asp134Argfs*49) was predicted to be deleterious by several in silico tools and classified as pathogenic (PVS1 and PM2) (PMC4544753). Unaffected parents and relatives are heterozygous for this CLPP variant or wild-type. The p.(Asp134Argfs*49) variant is absent in gnomAD v4.0.0 and not detected in 286 Pakistani control chromosomes. There have been few affected females with biallelic truncating variants of CLPP. Twenty-one CLPP variants are associated with deafness or PRLTS (Figure 1B) of which four variants including p.(Asp134Argfs*49) are predicted to truncate CLPP protein, if nonsense-mediated decay is incomplete. Sex and phenotype were not reported for c.270+3G>T (PMC7443947) and phenotype was not provided for c.270+4A>G (PMC3617381). We report two females homozygous for Asp134Argfs*49 of CLPP who have severe PRLTS characterized by profound SNHL, POI, and a brain MRI showing bilateral symmetric abnormal white matter signals within frontal, parietal and occipital lobes, similar MRIs of two reported deaf males.4 Our study expands the allelic and phenotypic spectrum of CLPP in females.5 We posit that severe PRLTS results from biallelic potential null-alleles of CLPP while hypomorphic variants are associated with SNHL alone or SNHL and POI. RF, RJM, SR, WGN, PS, NS, TBF performed experiments, data analyses and drafted the manuscript; resources and funding, TBF, SR, RJM; subject ascertainment, SR, AAK, MAU. We thank family participants and Dr. Rabia Tariq Qureshi, Jinnah Hospital, Lahore, and Dennis Drayna and Mhamed Grati for critiques. This research was supported, in part, by the Intramural Research Program of the NIH, NIDCD, DC000039 to TBF, Higher Education Commission of Pakistan to SR, Medical Research Council (MR/W019027/1) and NIHR Manchester Biomedical Research Centre (NIHR203308) to WGN. The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/cge.14514. The data that support the findings of this study are openly available in Clinvar at https://www.ncbi.nlm.nih.gov/clinvar/, reference number SUB13851436.