The missense mutation Y65C in polyglutamine-binding protein 1 (PQBP1) is associated with Renpenning syndrome, characterized by X-linked intellectual disability and microcephaly. However, the pathogenic mechanism underlying the microcephaly induced by the Y65C mutation remains unclear. In this study, we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C mutation impairs the proliferation of apical progenitors and their subsequent transition to basal progenitors, resulting in microcephaly and cognitive deficits like those observed in Renpenning syndrome patients. This Y65C substitution induces PQBP1 misfolding, which reduces PQBP1 protein levels and consequently impedes apical progenitor proliferation. Unexpectedly, the Y65C mutation also induces a gain-of-function that interferes with the transition from apical to basal progenitors by enhancing interactions with the core components of the mRNA 3' end processing machinery, thereby preserving proliferative alternative polyadenylation (APA) profiles. Our study demonstrates that a combination of loss-of-function and gain-of-function contributes to the microcephaly caused by the Y65C mutation.

Renpenning syndrome is a rare X-linked genetic disorder caused by variants in the PQBP1 gene, but the information about its prenatal presentation is very limited. A 35-year-old woman experienced two male pregnancies with thickened nuchal translucency (NT) (5.5 mm and 5 mm). She went to our prenatal diagnosis center for the current natural conception during the second pregnancy. Trio-whole exome sequencing (TrioWES) of chorionic villus biopsy revealed a 666-bp genetic deletion (chrX:48755195-49760422) in the fetus, inherited from the mother, which included TIMM17B and PQBP1. The couple opted for termination of pregnancy. During the third pregnancy, systematic fetal screening was performed in early pregnancy. An ultrasound examination at 12+1 weeks revealed a thickened NT (6.5 mm), nasal bones abnormalities and a cleft palate. Ultrasound examination at 16 weeks showed ventricular septal defect (VSD), and mild enlargement of the lateral ventricles in the fetus. Chorionic villus biopsy samples were tested for Multiplex Ligation-dependent Probe Amplification (MLPA), showing a 666-bp genetic deletion, inherited from the mother. The couple opted for termination of pregnancy, and the male fetus had a sunken nose and cup-shaped ears leading to a diagnosis of Renpenning syndrome. In conclusion, this emphasized the importance of early systematic pregnancy screening. Increased NT in the first trimester, especially when present in conjunction with ultrasound structural abnormalities such as nasal bone abnormalities, VSD, and mild bilateral ventriculomegaly, emphasized the importance of genetic testing, including chromosome testing, genomic testing, and Whole-exome sequencing.

To explore the genetic etiology of a child with Renpenning syndrome (RS), and review the literature on the clinical characteristics and gene mutations of RS. A child with RS (patient 1) who was diagnosed and treated in the Pediatric Intensive Care Unit of the Third Affiliated Hospital of Zhengzhou University in November 2023 was selected as the research object. The medical history, family history, physical examination, cerebrospinal fluid examination, echocardiography, brain magnetic resonance imaging (MRI), brain magnetic resonance angiography, cardiac coronary CT angiography and intelligence quotient (IQ) score of child 1 were retrospectively collected. Peripheral venous blood samples were collected from patient 1, his parents, sister and brother, respectively. Genomic DNA was extracted from the child and his family members, and Trios-whole exome sequencing (Trios-WES) was performed. Sanger sequencing was used to verify the pedigree. Bioinformatics softwares (Mutation Taster, REVEL, SIFT, PolyPhen-2, GERP++, SWISS-MODEL) were applied. The pathogenicity of the detected variants was rated according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the ACMG Guidelines). "PQBP1 gene" "Renpenning syndrome" "PQBP1 gene" "Renpenning syndrome" were used as keywords in Chinese and English, respectively. Case reports of patients with RS caused by PQBP1 gene variants were retrieved from Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed database. The clinical features and gene variants of RS caused by PQBP1 gene variants were summarized and analyzed. This study was reviewed by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Approval No. 2024-334-01). The patient 1, a 12-year-old boy, was admitted to the hospital due to fever and disturbance of consciousness. Cerebrospinal fluid test showed viral encephalitis caused by human herpesvirus 7 infection. The main clinical manifestations were unusual facies (microcephaly, long narrow face, microphthalmos, superior oblique palpebral fissure, hypertelorism of inner canthus, bulbous nasal columella) and mental retardation. Auxiliary examination showed than patient 1 had atrial septal defect, nodular heterotopia in the posterior horn of the left ventricle, angiodysplasia, and low IQ. The disease began in infancy, and there was no family history of related diseases. A hemizygous deletion, c.459_462del (p.Arg153SerfsTer41), was identified in exon 5 of the PQBP1 gene in patient 1, which was inherited from his mother by Sanger sequencing. The results of bioinformatics analysis showed that the mutation was harmful. This variant was rated as pathogenic (PVS1+PS4+PM2_Supporting+PP3) according to ACMG Guidelines. According to the literature search strategy set in this study, a total of 13 cases of RS were retrieved, involving 16 cases of RS patient caused by PQBP1 gene mutation (patients 2-17), including patient 1, a total of 17 cases of RS. Among the 17 patients, 16 male patients had hemizygous mutations in the X chromosome PQBP1 gene, and 1 female patient had heterozygous mutations, including 12 deletion frameshift nonsense mutations, 3 point missense mutations, and 2 duplication mutations. Except for two fetuses, all patients had special facial features and low IQ to varying degrees. Ten patients had abnormal development of one or more organs such as eyes, heart, brain, etc. CONCLUSION: The main clinical manifestations of RS are developmental delay, long narrow face, bulbous nose, microcephaly, and may be accompanied by heterotopia of gray matter of ventricle and congenital heart disease. The c.459_462del (p.Arg153SerfsTer41) variant of the PQBP1 gene is the genetic basis of patient 1 in this study.

Renpenning syndrome is a rare X-linked intellectual disability (XLID) caused by mutations in the polyglutamine-binding protein 1 (PQBP1) gene. Current understanding of its clinical features and pathogenesis remains limited, especially neuropsychological profile have not been fully investigated. We report a pair of Chinese siblings with Renpenning syndrome carrying a missense variant of PQBP1. They presented with severe intellectual deficiency, microcephaly, characteristic facial dysmorphism, short statures and lean body build. Neuropsychological assessment showed overall delayed development. Brain MRI scans indicated demyelination in which one patient exhibited improvement over a 6-year period. Both siblings experienced recurrent febrile convulsions before 5 years old, however, a diagnosis of epilepsy was not established. Notably, one child presented with multiple episodes of Henoch-Schönlein purpura (HSP), which has not been reported previously. Whole-exome sequencing identified a novel variant: C.28C > G (p.R10G) inherited maternally. Consequently, we report the first known Chinese cases of Renpenning syndrome, caused by a novel variant in PQBP1 gene. Our study has expanded the spectrum of PQBP1 variants and existing understanding of the neuropsychological phenotype.