Abstract

Background:

Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features.

Methods:

Comprehensive clinical evaluation and whole exome sequencing were performed to identify the genetic basis of the clinical presentation in a 4-year-7-month-old male proband from a Chinese family. Detected variants underwent validation and familial segregation analysis by Sanger sequencing. Additionally, a literature review was conducted to analyze PQBP1-related genotype-phenotype correlations.

Results:

The proband exhibited typical manifestations of Renpenning syndrome, including severe global developmental delay, microcephaly, short stature, and characteristic facial features. Additionally, he presented with rare anal atresia and co-occurring autism spectrum disorder (ASD). Whole exome sequencing identified a hemizygous PQBP1 frameshift variant, NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79), in the proband. Sanger sequencing confirmed this variant was maternally inherited.

Conclusion:

This report describes the first Chinese case of Renpenning syndrome caused by the PQBP1 c.459_462delAGAG variant, presenting with the core phenotype plus anal atresia and ASD. This case expands recognition of the clinical spectrum associated with PQBP1 variants.

1 Introduction

Intellectual disability (ID) is a significant public health issue that profoundly impacts society and families, with a global prevalence estimated at approximately 1%–3% (Gécz et al., 2009; Basel-Vanagaite, 2008). Notably, the X chromosome constitutes only 4% of the human genome. However, its genes are associated with about 10%–15% of genetic cases of ID (Ro and pers, 2008; Ropers and Hamel, 2005). Furthermore, about 10%–12% of male ID cases are attributed to pathogenic mutations on the X chromosome (De Luca et al., 2020; Ropers, 2010). Renpenning syndrome, caused by mutations in the polyglutamine-binding protein 1 (PQBP1) gene, represents one of the extremely rare genetic forms of X-linked intellectual disability (XLID). This syndrome was initially identified through intensive research into specific genetic pedigrees. In 1962, Renpenning’s team reported a large family spanning three generations, comprising 20 male patients who exhibited moderate to severe ID, short stature, microcephaly, dysmorphic facial features, and small testes, with no abnormalities observed in female family members (Renpenning et al., 1962). This groundbreaking study established the first direct link between ID and sex. In 2003, Kalscheuer et al. identified PQBP1 mutations in 5 out of 29 XLID families, thereby confirming the pathogenicity of this gene (Kalscheuer et al., 2003). Subsequently, PQBP1 mutations have been implicated in a range of related syndromes, including Golabi-Ito-Hall syndrome, Sutherton-Haan syndrome, Hamel-cerebro-palato-cardiac syndrome, Porteous syndrome, and non-syndromic intellectual disability (MRX55), as well as in three smaller families without reported phenotypes (Stevenson et al., 2005; Lubs et al., 2006). To honor the pioneering work of the Renpenning team, XLID caused by PQBP1 mutations was officially designated as Renpenning syndrome in 2005 (Stevenson et al., 2005).

Due to the rarity of Renpenning syndrome and the incomplete understanding of its pathogenic gene PQBP1, the global understanding of this disorder relies heavily on small-scale studies and case reports from predominantly Western populations. This study presents a case of PQBP1 gene mutation in a Chinese male patient and conducts a systematic review of existing literature. Through this analysis, the study highlights the potential phenotypic characteristics of this mutation in Asian populations, with the aim of enhancing clinicians’ awareness of the disease and providing valuable insights for diagnostic considerations.

2 Study subjects and methods2.1 Study subjects

This study included a 4-year-7-month-old boy (the proband) who was admitted to the Child Growth and Health care Clinic of Fuyang People’s Hospital due to developmental delay in November 2024. The G5P4 patient was born by cesarean section at 40 weeks of gestational age with a birth weight of 3 kg and a birth length of 45 cm. Prenatal ultrasound revealed an occipitofrontal circumference (OFC) that was below the expected range for gestational age. There was no history of asphyxia or pathological jaundice at birth. Additionally, there was no history of intrauterine infection, perinatal hypoxia and asphyxia or drug exposure during pregnancy. His able-bodied, non-consanguineous parents had four children: two boys and two girls (Figure 1A). His two elder sisters were of normal intelligence, while his elder brother suffered from ID and died prematurely.

(A) Family pedigree: Affected males are indicated by black squares, whereas the dots indicate obligate carriers. The deceased is indicated by a slash. The arrow signifies the proband. (B) The facial image shows the patient with triangular face, prominent large ears, epicanthal folds, sparse eyebrows, broad nasal bridge with bulbous tip, thin upper lip, and characteristic nasal speech. (C) Polyglutamine-binding protein 1 (PQBP1) mutation in our case: Father (II-8): no variation in PQBP1 gene. The proband (III-7): PQBP1 c.459_462delAGAG. Mother (II-7): heterozygous. (D) Polyglutamine-binding protein 1 (PQBP1) mutation in our case: The maternal grandmother (I-1) and sisters (III-4 and III-5): heterozygous. (E) Representation of domain structure and mutations in polyglutamine-binding protein 1 (PQBP1). The detected mutation c.459_462delAGAG is shown in the red frame. 22 PQBP1 mutations were identified in previous cases, 3 mutations were not marked in the domain due to the absence of detailed data: 4.7 Mb duplication of PQBP1 at Xp11.22–p11.23; de novo 5 Mb duplication of PQBP1 at Xp11.22-p11.23; Xp11.2-q12. WWD, WW domain; PRD, polar amino acid-rich domain; CTD, c-terminal domain; NLS, nuclear localization signal (Figure 1E is reproduced from original illustration created by Mengting Zhang on FigDraw, with permission under copyright code TUWYR13692, by figdraw.com).

2.2 Methods2.2.1 Clinical data analysis

The clinical data of the proband were collected, general physical examination and specialist examination were performed, and the examination results of other hospitals and our hospital were collected, including a variety of assessment scales, genetic testing, imaging examination (brain CT, brain MRI, electroencephalogram, urinary tract color Doppler ultrasound), visual acuity and hearing test data.

2.2.2 Whole exome sequencing (WES) and sanger sequencing verification

Peripheral blood was collected from the child in EDTA anticoagulant tubes. Genomic DNA was extracted using the Vazyme DNA extraction kit (#VNP-32P). DNA concentration was determined with the Yisheng Bio-dsDNA HS Assay Kit (batch 12642ES76). Sequencing libraries were constructed using the Vazyme Universal Plus DNA Library Prep Kit for MGI (V2). Target regions were captured using the EGI-Taikang Ai full-exome V3 capture kit, followed by paired-end sequencing on a BGI T7 sequencer to generate FASTQ data. Alignment was performed against the human reference genome (hg19). Data filtering used fastp, and sequence alignment used BWA. Variant database correction employed dbSNP (v159). Sequencing depth and coverage were assessed using samtools depth and GATK DepthOfCoverage. Quality control required an average depth ≥100X and ≥95% coverage at 20X. Variant calling was performed with GATK (v3.8), and GC content analysis was performed with mosdepth (v0.2.5). Variant annotation utilized ANNOVAR, integrating HGMD, HPO, and internal databases. Pathogenicity classification followed ACMG guidelines. Peripheral blood samples from the patient’s parents, siblings, and maternal grandmother underwent Sanger sequencing. Primers were designed using Primer-BLAST, amplified by PCR, purified via electrophoresis, and sequenced bidirectionally on an ABI sequencer. Sequence traces were analyzed with Chromas software.

2.2.3 Literature review

A systematic search of PubMed, Web of Science, and Cochrane Library was conducted to identify relevant reports published from inception through February 2025. Search terms included “Renpenning syndrome,” “PQBP1,” “Golabi-Ito-Hall syndrome,” “Sutherland-Haan syndrome,” “Hamel cerebro-palato-cardiac syndrome,” “Porteous syndrome,” and “MRX55.” References of the included articles were also manually searched for potential studies. Only case report-related literature was included, excluding (1) reviews, mechanistic studies, other studies not related to clinical cases, and literature for which full text was not available, and (2) non-English language literature.

3 Results3.1 Clinical data analysis

The boy was evaluated in November 2024 for speech delay and global developmental concerns. On physical examination, the child was conscious, energetic, and appeared moderately nourished. Objective measurements revealed microcephaly (OFC 46.5 cm, < −3 SD), short stature (height 99.8 cm, < −2 SD), and lean body (weight 13 kg, < −3 SD). The special examination found that the child could only speak short sentences, had poor initiative social ability, less eye contact, liked to play alone, lacked joint attention, and could not participate in group games. He also showed marked difficulties in cognitive comprehension, especially with number and color recognition, despite being able to follow simple instructions. Moreover, he often engaged in self-talk and repetitive behaviors such as spinning in circles. There were no obvious abnormalities in muscle strength and muscle tension of the limbs. He has the characteristics of a triangular face, prominent and large ears, wide inner canthus, epicanthus, semi-depilated eyebrow, bulbous nose, broad nasal bridge, thin upper lip, and nasal speech (Figure 1B). The patient has clinical diagnoses of global developmental delay (based on the Gesell assessment), microcephaly (OFC < −3 SD), short stature (height < −2 SD), and autism spectrum disorder (ASD, based on DSM-5 criteria). He regularly receives rehabilitation, including weekly speech therapy.

3.2 Results of clinical assessment

The patient’s significant developmental and behavioral impairments were evident across standardized assessments. Performance was in the severe range as evidenced by a Childhood Autism Rating Scale (CARS) score of 35 (moderate autism), an Autism Behavior Checklist (ABC) score of 88, and a standardized score of 5 on the Infant-Junior Middle School Student Activities of Daily Living (ADL) Scale, the latter indicating extremely severe impairment in daily functioning. Cognitive evaluations revealed significantly below-average scores. On the Wechsler Intelligence Scale for Children-Second Edition (WISC-II), the patient achieved a full-scale IQ of 52, with verbal and performance scores of 56 and 55, respectively. The Gesell Developmental Assessment (GDA) yielded a total score of 35, with subdomain scores as follows: language (29), adaptive behavior (43), gross motor (62), fine motor (53), and social competence (55). The Chinese Psychoeducational Profile-Third Edition (CPEP-3) revealed severe developmental delays in cognition (standard score 25), expressive language (17), and personal self-care (28). Moderate delays were noted across receptive language, motor skills, affective expression, social interaction, and adaptive behavior, while visual-motor imitation showed only a mild delay. Composite scores confirmed a severe delay in communication (total score 22, developmental age 20.7 months), with moderate delays in both motor (total score 33, developmental age 35.7 months) and social behavior (total score 38) domains. Additionally, the Imaginative Play Assessment (IPA) score of 4 corresponded to developmental functioning below 12 months of age.

3.3 Imaging and other examination results

Brain CT and MRI revealed no structural abnormalities. Electroencephalogram showed normal cortical activity, and urinary tract Doppler ultrasonography demonstrated unremarkable findings. Audiometric testing indicated normal hearing thresholds. Ophthalmologic evaluation identified bilateral refractive errors: hypermetropia (right eye: +2.75 D, left eye: +3.50 D) with compound astigmatism (right eye: −3.50 D, left eye: −0.25 D). Standard karyotyping confirmed a 46, XY chromosomal constitution. Chromosomal microarray analysis (CMA) detected no clinically significant copy number variations (CNVs).

3.4 Results of WES

WES showed that the proband carried a hemizygous frameshift mutation of PQBP1 gene NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79). Sanger sequencing confirmed that the hemizygous variant was inherited from his mother (heterozygous carrier), but not from his father (Figure 1C). The variant was rated as pathogenic according to ACMG guidelines (PVS1+PS3+PS4+PM2_Supporting + PP1). No CNV or chromosomal abnormalities related to the patient’s clinical phenotype were detected.

3.5 Family co-segregation verification

Sanger sequencing showed that the maternal grandmother and two elder sisters of the proband carried a heterozygous mutation of PQBP1 c.459_462delAGAG (Figure 1D), which was consistent with the X-linked recessive inheritance pattern.

3.6 Literature review

The human PQBP1 gene is located at Xp11.23 and encodes a 265-amino acid protein consisting of a WW domain (WWD), a polar amino acid-rich domain (PRD), and a C-terminal domain (CTD) with a nuclear localization signal (NLS) (Cheng et al., 2023). Summarizing the previously published literature, 22 mutations have been found in PQBP1 (Renpenning et al., 1962; Kalscheuer et al., 2003; Stevenson et al., 2005; Lubs et al., 2006; Deqaqi et al., 1998; Lenski et al., 2004; Bonnet et al., 2006; Cossée et al., 2006; Fichera et al., 2005; Martínez-Garay et al., 2006; Sheen et al., 2010; Germanaud et al., 2011; Rejeb et al., 2011; Flynn et al., 2010; Redin et al., 2014; Abdel-Salam et al., 2018; Jeo et al., 2018; Mameesh et al., 2019; Cho et al., 2020; Masih et al., 2019; Kurt et al., 2020; Aleksic et al., 2021; Murdock et al., 2021; Lopez-Martín et al., 2022; Kaymakçalan et al., 2022; Kanagavel and Manokaran, 2025; Pan et al., 2025). These mutations can be divided into five groups based on the domains affected: Missense mutations in the WWD, gross deletions in the PRD, AG nucleotide duplications or deletions affecting DR/ER repeats in the PRD, AG nucleotide deletions and nonsense mutations affecting the NLS, and insertion and missense mutations in the CTD. Additional details of included studies are shown in Table 1; Figure 1E.

ReferencesSyndrome/familyClinVar IDMutationDomainClinical featuresRenpenning et al. (1962)original familyVCV004795965.1c.641insC*C-terminal regionID, microcephaly, long face, short stature, lean body, small testesKalscheuer et al. (2003),Deqaqi et al. (1998)MRX55VCV000010980.79c.459_462delAGAGDR/ER repeatID, short statureKalscheuer et al. (2003)N45VCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic facies, anal atresia, complete situs inversusKalscheuer et al. (2003)Hamel cerebro-palato-cardiac (N40)VCV000010981.7c.461_462delAGDR/ER repeatID, microcephaly, short stature, long face, lean body, congenital heart defectKalscheuer et al. (2003)Sutherland_Haan syndromeVCV000010979.11c.463_464dupAG*DR/ER repeatID, microcephaly, short stature, long face, lean body, small testes, anal stenosis or atresiaKalscheuer et al. (2003)N09VCV000010979.11c.463_464dupAG*DR/ER repeatID, microcephaly, long face, lean bodyLenski et al. (2004)K9008VCV001691229.3c.575_576delAGNLSID, microcephaly, short stature, long face, lean bodyStevenson et al. (2005)K8600VCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, lean body, dysmorphic facies, small testes, developmental delayStevenson et al. (2005)Porteous syndromeVCV000010979.11c.463_464dupAG*DR/ER repeatID, long face, lean bodyLubs et al. (2006)Golabi_Ito_Hall (K8275 family)VCV000010985.4c.194A>GWWDID, microcephaly, lean body, short stature, postnatal growth deficiency, atrial septal defect, spastic diplegia, triangular faceCossée et al. (2006)F1VCV000010983.1c.547_569delAfter the DR/ER repeatID, microcephaly, lean body, dysmorphic facies, bilateral choanal atresia, and anal atresiaCossée et al. (2006)F2, F3 and F4VCV000010984.32c.334_354delPRDID, behavioral anomaliesCossée et al. (2006)F5VCV000284597.20c.393_413delPRDID, microcephaly, lower limbs spasticityMartínez-Garay et al. (2006)Martinez_Garay familyVCV000010981.7c.461_462delAGDR/ER repeatID, microcephaly, short stature, microphthalmiaSheen et al. (2010)Sheen familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, dysmorphic facies, hearing loss, periventricular heterotopiaGermanaud et al. (2011)P familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic facies, muscular atrophyGermanaud et al. (2011)CB familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic facies, muscular atrophyGermanaud et al. (2011)S familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic faciesGermanaud et al. (2011)B familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic facies, muscular atrophyGermanaud et al. (2011)AH familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic faciesGermanaud et al. (2011)L familyVCV000545093.14c.586C>TNLSID, microcephaly, short stature, lean body, dysmorphic facies, muscular atrophyRejeb et al. (2011)Tunisian familyVCV004795964.1c.631insA*C-terminal regionID, microcephaly, long face, short stature, lean bodyJeo et al. (2018)Korean familyVCV004795963.1c.559delTNLSID, short stature, and microcephalyRedin et al. (2014)Autism likedVCV000235848.3c.731C>TC-terminal regionModerate ID, poor autonomy, communication and social interaction disorders, learning difficulties, autistic behaviorAbdel-Salam et al. (2018)North African familyVCV001527945.4c.530G>AAfter the DR/ER repeatthe frontal and bitemporal baldness, bulbous nose, long palpebral fissures, cupped ears, pre_auricular tags, simple helix and pitted ear lobules, partial agenesis of the corpus callosumMameesh et al. (2019)Omani familyVCV000284240.7c.450_453delDR/ER repeatmicrocephaly, mild short stature, triangular face, unilateral microphthalmos, large bulbous nose, cup_shaped ears, short philtrumCho et al. (2020)a female patientVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, lean body, dysmorphic facies, hearing loss, and unilateral microphthalmia with cataractMasih et al. (2019)an Indian patientVCV000010980.79c.459_462delAGAGDR/ER repeatmicrocephaly, short stature, lean body, dysmorphic facies, developmental delay, progressive atrophy of the upper back muscles, loss of cervical lordosis, and upper thoracic scoliosisKurt et al. (2020)a Turkish PatientVCV001308367.8c.640C>TC_terminal regionID, microcephaly, short stature, small testes, dysmorphic facies, speech and language problems, patent foramen ovale, recurrent urinary tract infections and bronchitis, hypogammaglobulinemiaAleksic et al. (2021)Serbian familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, dysmorphic facies, cardiac abnormalities, developmental delay, seizures, asymmetric cerebellar hemispheresMurdock et al. (2021)A male child patientVCV000977747.2c.180-306G>AWWDID, microcephaly, short stature, lean body, dysmorphic facies, developmental delay, congenital heart defects (ventricular septal defect and patent ductus arteriosus), vertebral anomalies (butterfly vertebrae), ectopic pelvic left kidney, hypospadias, sensorineural hearing lossLopez-Martín et al. (2022)Spanish familyVCV000977914.4c.727C>TC_terminal regiondysmorphic facies, Attention_deficit/hyperactivity disorder, borderline intellectual functioning with marked language impairmentKaymakçalan et al. (2022)Turkish familyVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, dysmorphic facies, congenital heart disease, developmental delayKanagavel and Manokaran (2025)an Indian patientVCV000010980.79c.459_462delAGAGDR/ER repeatID, microcephaly, short stature, long face, lean body, dysmorphic facies, developmental delayPan et al. (2025)Chinese familyVCV004795962.1c.28C>Goutside the usual functional regionsID, microcephaly, short stature, lean body, dysmorphic facies, developmental delay, speech delay, eecurrent febrile convulsions, henoch_schonlein purpura, allergic reaction, memory impairment, brain MRI scans indicated demyelination

PQBP1 mutation sites and clinical features in patients with Renpenning syndrome.

Abbreviation: ID, intellectual disability.

*

Variant nomenclature has been updated to conform to current HGVS, guidelines. In the ClinVar records: c.641insC has been revised to c.641_642insC; c.631insA has been updated to c.632dup; and c.463_464dupAG, has been revised to c.461_462dupAG.

After a detailed search, nine case reports (Kalscheuer et al., 2003; Stevenson et al., 2005; Sheen et al., 2010; Germanaud et al., 2011; Cho et al., 2020; Masih et al., 2019; Aleksic et al., 2021; Kaymakçalan et al., 2022; Kanagavel and Manokaran, 2025) of c.459_462delAGAG mutations in the PQBP1 gene were included, totaling 27 patients. All cases had moderate to severe ID except for one adult male patient who did not undergo routine intelligence testing. Additionally, developmental delay constituted the most frequent manifestation at 96%, followed sequentially by microcephaly in 89% of patients, lean body build in 70%, and short stature in 67%. Characteristic dysmorphic facial features included a long, triangular, or narrow face; large and cupped ears; a bulbous, large, or prominent nose; and sparse lateral eyebrows. The remaining details are shown in Table 2 and Table 3.

Referencessyndrome
/FamilyAncestryNumber of casesIDMicroce-phalyShort statureLean bodySmall testisDevelop-mental delayDysmorphic faceAnal atresiaCardiac anomalyOthersMutation originKalscheuer et al. (2003)MRX55Moroccan3+-+--+Large narrow face, bulbous nose, short philtrum, and overhanging columella---NKalscheuer et al. (2003)N45Dutch3++++-+Long narrow face, malar hypoplasia, prognathism, large or protruding ears, high-arched palate, upslanting palpebral fissures, and nasal speech+-Complete situs inversusNStevenson et al. (2005)K8600N4++-+++Upslanting palpebrae, long narrow face, large cupped ears, cleft palate, central balding, and epicanthus-+Autism spectrum disorder, depression, systolic and diastolic heart murmurs, hypertension and mitral valve prolapse in adulthoodNSheen et al. (2010)sheen familyAfrican
American2+++--+Broadened nose, narrow chin, freckled tongue, low-set and cupped ears--Impaired hearing, mild cognitive impairment, chronic cough, flat feet, multiple sub-centimeter pulmonary nodules on chest CT, and nodular gray matter heterotopia along the trigones of the lateral ventricles on MR imagingmaternalGermanaud et al. (2011)P familyFrench1++++-+Long or triangular face, sparse lateral eyebrows, ears (large, protruding, mildly dysplastic), thin upper lip, prognathism/micro retrognathism jaw, long/curved eyelashes, and malar hypoplasia--Muscular atrophy (back), hypermetropia, strabismus, terminal spine defect, MCP-1 ankylosis, velar dysfunctionNGermanaud et al. (2011)CB familyFrench2++++++Long or triangular face, sparse lateral eyebrows, ears (large, protruding, mildly dysplastic), rough and slightly sparse hair, prominent and large nose, prognathism/micro retrognathism jaw, and long/curved eyelashes+-Muscular atrophy (back and hand), phimosis, lower pyramidal signs, terminal spine defect, MCP-1 ankylosis, velar dysfunction, autism spectrum disorderNGermanaud et al. (2011)S familyFrench2++++-+Long or triangular face, sparse lateral eyebrows, ears (large, protruding, mildly dysplastic), rough and slightly sparse hair, prominent and large nose, thin upper lip, upslanting palpebral fissures, and malar hypoplasia-+Muscular atrophy (back), pronosupination restriction, horseshoe kidney, phimosis, strabismus, lower pyramidal signs, hypermetropia, terminal spine defect, MCP-1 ankylosis, velar dysfunctionNGermanaud et al. (2011)B familyFrench2++++-