U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

PUF60-Related Disorders

, , , PhD, , PhD, and , MD.

Author Information and Affiliations

Initial Posting: .

Estimated reading time: 28 minutes

Summary

Clinical characteristics.

The phenotypic spectrum in individuals with a genetic alteration involving PUF60 (i.e., PUF60-related disorders) is a continuum in which most individuals have mild-to-moderate developmental delay with variable multisystem features, most commonly short stature, muscular hypotonia, and skeletal involvement. Rarely, individuals with a genetic alteration involving PUF60 have multisystem involvement that was initially described as Verheij syndrome, a clinically defined phenotype involving severe neurodevelopmental delay with pronounced multisystem involvement including seizures, coloboma, congenital cardiac defects, short stature, and skeletal anomalies. To date, 84 individuals have been identified with a PUF60-related disorder.

Diagnosis/testing.

The diagnosis of a PUF60-related disorder is established in a proband with suggestive findings and either a heterozygous pathogenic variant in PUF60 or a contiguous gene deletion of 8q24.3 including PUF60 identified by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care by specialists in relevant fields including clinical genetics and pediatric specialists and allied health professionals in neurology, audiology, ophthalmology, development (including physical therapy and speech-language pathology), feeding, cardiology, pulmonology, gastroenterology, immunology, endocrinology, nephrology, urology, and orthopedics.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, regularly scheduled follow-up appointments with treating specialists are recommended.

Genetic counseling.

PUF60-related disorders are autosomal dominant disorders typically caused by a de novo genetic alteration (either a pathogenic variant in PUF60 or a contiguous gene deletion of 8q24.3 including PUF60). Rarely, individuals diagnosed with a PUF60-related disorder have the disorder as the result of a genetic alteration inherited from a parent. Each child of an individual with a PUF60-related disorder has a 50% chance of inheriting the causative genetic alteration. Once the genetic alteration involving PUF60 has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for PUF60-related disorders have been published.

Suggestive Findings

A PUF60-related disorder should be considered in probands with the following suggestive clinical and brain MRI findings and family history.

Clinical Findings

Core neurodevelopmental manifestations

  • Developmental delay, typically with significant delay of speech, variable motor delay in gross and fine motor skills, and/or intellectual disability / learning disabilities
  • Neurobehavioral manifestations, which may include attention-deficit/hyperactivity disorder, aggressive behavior, emotional disorders, sensory issues, and/or autism spectrum disorder

Variable multisystem findings

  • Short stature. Growth delay or intrauterine growth restriction are also common.
  • Skeletal involvement
    • Spinal abnormalities including scoliosis and vertebral fusion defects
    • Pectus excavatum, Sprengel anomaly, and congenital hip dysplasia
    • Abnormalities of the hand including brachydactyly and clinodactyly
    • Abnormalities of the foot including pes planus
    • Joint hypermobility
  • Microcephaly, either congenital or acquired
  • Ophthalmologic findings. Coloboma, optic nerve hypoplasia, impaired vision, amblyopia, strabismus
  • Hearing loss. Congenital sensorineural hearing loss is likely to be detected on newborn hearing screening; hearing loss with later onset is likely to be detected when prompted by specific concerns.
  • Neurologic involvement, including epilepsy, muscular hypotonia, and tremor
  • Dermatologic involvement, such as eczema, café-au-lait spots, hyper- and/or hypopigmented skin
  • ENT and dental involvement including high-arched palate, micrognathia, and dental crowding
  • Congenital structural cardiac abnormalities including ventricular septal defect, atrial septal defect, and tetralogy of Fallot
  • Congenital anomalies of the kidney and urinary tract, including renal agenesis
  • Genital anomalies, including cryptorchidism
  • Failure to gain weight and/or feeding difficulties, typically evident as little weight gain despite adequate caloric intake. Failure to gain weight may be associated with dysphagia, sensory issues, vomiting, and gastroesophageal reflux disease.
  • Gastrointestinal involvement, such as diarrhea, obstipation, and abdominal pain.
  • Immunologic involvement, including immune dysregulation manifesting as increased susceptibility to infections (i.e., recurrent pulmonary and/or gastrointestinal infections) in the first year of life or allergies (including eczema)

Brain Imaging

Brain MRI findings mostly include dysgenesis of the corpus callosum (15%) and white matter abnormalities (6%) [Baum et al 2024].

Other variable brain abnormalities include ventricular enlargement and cerebral atrophy, and less frequently posterior pituitary ectopia [Verheij et al 2009, Fennell et al 2022, Grimes et al 2023]. Rarely observed abnormalities may include cystic lesions and hydrocephalus.

Family History

Because PUF60-related disorders are typically caused by a de novo genetic alteration (either a pathogenic variant in PUF60 or a contiguous gene deletion of 8q24.3 including PUF60), most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of a PUF60-related disorder is established in a proband with suggestive findings and either a heterozygous pathogenic (or likely pathogenic) variant in PUF60 or a contiguous gene deletion of 8q24.3 including PUF60 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous PUF60 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis [CMA], exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of PUF60, followed by gene-targeted deletion/duplication analysis) to detect an 8q24.3 deletion that includes PUF60 is rarely useful and typically NOT recommended.

Option 1

A multigene panel that includes PUF60 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most used; genome sequencing is also possible. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025].

To date, the majority of PUF60 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including 8q24.3 deletions that include PUF60) that cannot be detected by sequence analysis.

For an introduction to CMA click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

PUF60-Related Disorders: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
PUF60 Sequence analysis 390% 4
Gene-targeted deletion/duplication analysis 51% 6
8q24.3 deletion that includes PUF60CMA 79% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Grimes et al [2023] and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.
7.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including PUF60) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 8q24.3 region. CMA designs in current clinical use target the 8q24.3 region.

Clinical Characteristics

Clinical Description

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of PUF60-related disorders represents a continuum in which most individuals have a mild-to-moderate phenotype primarily characterized by neurodevelopmental features with variable multisystem involvement, most commonly short stature, muscular hypotonia, and skeletal anomalies [Baum et al 2024]. Rarely, individuals with a genetic alteration involving PUF60 have a broader and more severe phenotype that was initially described as Verheij syndrome, a clinically defined phenotype involving severe neurodevelopmental delay with pronounced multisystem involvement (see Nomenclature) [Verheij et al 2009].

To date, 84 individuals have been identified with either a PUF60 pathogenic variant or a contiguous gene deletion of 8q24.3 that includes PUF60. These reports have mostly included individuals toward the milder end of the phenotypic spectrum [Baum et al 2024], while reports of the more severe end of the phenotype are rare [Verheij et al 2009]. Several additional clinical findings (e.g., immunologic or skin issues) are likely underdiagnosed and require further evaluation in future studies.

The following description of the phenotypic spectrum associated with PUF60-related disorders is based on clinical reports published to date.

Neurodevelopmental delay

  • Developmental delay, present in all reported individuals, ranges from mild to severe, manifesting as speech delay, gross and fine motor delay, and learning disability, as well as problems with concentration/focus [Grimes et al 2023, Baum et al 2024].
  • Intellectual disability, present in 68% of affected individuals, manifests as mild in most individuals [Grimes et al 2023].
  • Neurobehavioral manifestations. Most common are sensory issues (29%), attention-deficit/hyperactivity disorder (25%), and aggressive/frustrated behavior (17%) [Baum et al 2024]. Other less common features are self-injurious behavior (10%), movement stereotypies (8%), and autism spectrum disorder (7%) [El Chehadeh et al 2016, Baum et al 2024].

Neurologic

  • Muscle tone at the time of diagnosis may include hypotonia [Baum et al 2024].
  • Seizures, present in 24% of individuals, are mostly infrequent and may occur in the first years of life [Baum et al 2024, Kursat et al 2026].
    Although most seizures are well-controlled with anti-seizure medications (ASMs), the response can vary.
  • Movement disorders, which include tremor and nystagmus, are rare but most likely underdiagnosed [El Chehadeh et al 2016, Grimes et al 2023].

Skeletal involvement, present in 48% of individuals, is divided into appendicular and axial skeletal malformations.

  • Axial skeletal anomalies include spinal malformations, most commonly cervical defects (26%), scoliosis (21%), and hemivertebrae (12%). Less common findings are kyphosis, hyperlordosis, spina bifida occulta, and rudimentary ribs [Low et al 2017].
    Additionally, pectus excavatum and chest wall asymmetry have been reported [Grimes et al 2023].
  • Appendicular skeletal anomalies mostly include hand and foot abnormalities.
    Hand abnormalities include clinodactyly, preaxial polydactyly, and brachydactyly. Less frequent are broad hands [Low et al 2017].
    Foot abnormalities include pes planus, talipes equinovarus, and sandal gap deformity. Less common are deformities of the great toes, short feet, and duplication of the toes [Fennell et al 2022].
  • Other less common findings include congenital hip dysplasia, Sprengel deformity, and Klippel-Feil anomaly [Grimes et al 2023].
  • Joint hyperlaxity, present in 30% of individuals, is associated with a higher risk of subluxations or full dislocation as well as muscle tone problems [Baum et al 2024].

Palatal involvement. The most common features are micrognathia (24%) and a high-arched palate [Grimes et al 2023].

Short stature occurs in 68% of individuals; however, intrauterine growth restriction is only present in 24% [El Chehadeh et al 2016]. Another less common finding is delayed bone age [Fennell et al 2022].

Dermatologic involvement includes hypertrichosis (12%) and skin tags (11%) [Low et al 2017]. Other skin issues are café-au-lait spots, eczema, and hyperpigmented maculae [Sivasubramanian & Ayyavoo 2024].

Poor weight gain despite adequate caloric intake is common, with profound poor weight gain seen in many individuals. Poor weight gain may be further aggravated by feeding difficulties and dysphagia, present in 44% of individuals [Baum et al 2024]. Other gastrointestinal features include gastroesophageal reflux disease and vomiting with an increased risk for aspiration pneumonia [Dauber et al 2013]. Also, diarrhea and other features mimicking inflammatory bowel syndrome can be seen [Hoogenboom et al 2024].

Cardiac involvement includes mostly congenital heart defects, including ventricular septal defects in 21% and atrial septal defects in 12% [Low et al 2017, Hoogenboom et al 2024]. Other congenital heart defects reported in about 4%-8% of individuals include patent ductus arteriosus, tetralogy of Fallot, and valve involvement, including mitral valve insufficiency [Grimes et al 2023, Miao et al 2024].

Congenital anomalies of the kidney and urinary tract. Affected individuals can present with renal agenesis (6%) [Graziano et al 2017]. Polycystic kidneys, kidney hypoplasia, or fused kidneys are also reported [Dauber et al 2013]. Other features can include decreased kidney function. Abnormalities of the urinary tract include hydroureter, ureterocele, neurogenic bladder and vesicoureteral reflux [El Chehadeh et al 2016].

Genital abnormalities in males include cryptorchidism and scrotal hypospadias [Moccia et al 2018, Hoogenboom et al 2024].

Ophthalmologic features mainly include coloboma (25%), impaired vision (24%), strabismus (12%), amblyopia (7%), and optic nerve hypoplasia (6%) [Abdin et al 2019, Fennell et al 2022].

Refractive errors can include hyperopia (8%) [Zhao et al 2018]. Other reported ophthalmologic findings include myopia, exotropia, esotropia, and cataract.

Microcephaly, present in 27% of individuals, is mostly congenital [Dauber et al 2013].

Sensorineural hearing loss, present in 24% of individuals, may be detected shortly after birth using auditory brain stem response testing [Low et al 2017].

Additional ear manifestations include small ear canals and middle ear involvement often requiring tympanostomy tubes [Baum et al 2024].

Other multisystem involvement in less than 20% of affected individuals that are probably underreported include the following:

Possible immunologic involvement. Recurrent infections that may occur in infancy and early childhood include ear infections, pneumonia, laryngitis, and recurrent flu-like infections [Baum et al 2024]. Other features may include eczema, acne, keratosis, macular skin rashes, asthma, and food allergies.

Prognosis. It is not known if the life span of individuals with a PUF60-related disorder is abnormal. One reported individual is alive at age 49 years [Grimes et al 2023], demonstrating that life span does not seem to be severely affected to date. Since adults with a PUF60-related disorder may not have undergone advanced genetic testing, adults may be underrecognized and underreported.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

The term Verheij syndrome is based on the original publication by Verheij et al [2009] describing two individuals with multigene deletions and severe neurodevelopmental delay with pronounced multisystem involvement (coloboma, congenital cardiac defects, seizures, short stature, skeletal anomalies, microcephaly, craniofacial dysmorphia, and congenital anomalies of the kidney and urinary tract). Several case series have identified PUF60 as the main driver in the monogenic cause of Verheij syndrome and partly reiterated the phenotypic findings described in the original publication.

In recognition of the wide phenotypic spectrum now known to be associated with intragenic PUF60 pathogenic variants, Baum et al [2024] proposed PUF60-related disorders as an umbrella term to encompass all phenotypes associated with genetic alterations involving PUF60, including clinically defined Verheij syndrome as well as mild and moderately severe phenotypes.

Prevalence

The birth prevalence for PUF60-related disorders is unknown. To date, more than 80 individuals have been reported with a PUF60-related disorder.

Differential Diagnosis

The differential diagnosis of PUF60-related disorders depends on the presenting features. Disorders of known genetic cause with features overlapping those of PUF60-related disorders are summarized in Table 3a.

Table 3a.

PUF60-Related Disorders: Genetic Differential Diagnosis

Gene(s) / Genetic MechanismDisorderMOIFeatures Similar to PUF60-Related DisordersFeatures Distinct from PUF60-Related Disorders
ARID1A
ARID1B
ARID2
BICRA
DPF2
PHF6
SMARCA2
SMARCA4
SMARCB1
SMARCC2
SMARCD1
SMARCE1
SOX4
SOX11 		Coffin-Siris syndrome AD
  • Facial features (thick eyebrows, wide mouth)
  • DD/ID
  • Hypoplasia of 5th digit finger/toe or nail
  • More prominent behavioral issues
BRAF
KRAS
LZTR1
MAP2K1
MRAS
NRAS
PTPN11
RAF1
RASA2
RIT1
RRAS2
SOS1
SOS2 		Noonan syndrome AD
(AR 1
  • Cardiac anomalies
  • Short stature
  • Mild DD
  • Webbed neck
  • Bleeding diathesis
  • Characteristic Noonan syndrome facial appearance
BRD4
HDAC8
NIPBL
RAD21
SMC1A
SMC3 		Cornelia de Lange syndrome AD
XL
  • Skeletal anomalies (e.g., brachydactyly, clinodactyly, & joint laxity)
  • Short stature
  • DD/ID
  • Craniofacial features
Self-injury tendencies
CHD7 CHARGE syndrome (See CHD7 Disorder.)AD
  • Coloboma
  • Congenital heart defects
  • Short stature
  • DD/ID
  • Facial asymmetry
  • Choanal atresia
  • Cranial nerve dysfunction
CREBBP
EP300 		Rubinstein-Taybi syndrome AD
  • Congenital heart defects
  • Facial features
  • DD
More severe ID & behavioral issues
FGD1 FGD1-related faciogenital dysplasia (Aarskog-Scott syndrome) XL
  • Short stature
  • Facial features
  • DD
  • Shawl scrotum
  • Brachydactyly
  • Widely spaced eyes
GDF3
GDF6
MEOX1
MYO18B 		Klippel-Feil syndrome (OMIM PS118100)AD
AR
  • Skeletal anomalies (esp involving cervical region)
  • Short neck
Limited neck mobility
JAG1
NOTCH2 		Alagille syndrome AD
  • Vertebral anomalies (e.g., hemivertebrae & cervical defects)
  • Cardiac anomalies
  • Facial features
  • Hepatic cholestasis (bile duct paucity)
  • Butterfly vertebrae
KDM6A
KMT2D 		Kabuki syndrome AD
XL
  • Craniofacial features
  • Congenital anomalies (incl heart & kidneys)
  • DD/ID
  • Arched eyebrows
  • Persistent fetal fingertip pads
MYCN Feingold syndrome 1 AD
  • Microcephaly
  • Learning disability
  • Toe syndactyly
  • Esophageal/duodenal atresia
TFAP2A Branchiooculofacial syndrome AD
  • Coloboma
  • Broad nasal tip
  • Branchial clefts or cysts
  • Upper lip pits
4p16.3 deletionWolf-Hirschhorn syndrome (OMIM 194190) De novo
  • ID
  • Facial features
  • Seizures
"Greek warrior helmet" face
Mosaic tetrasomy 12pPallister-Killian syndrome (OMIM 601803) De novo
  • Facial features (e.g., long philtrum, broad nasal bridge, palpebral fissure)
  • ID
  • Pigmentary skin anomalies
  • Diaphragmatic hernia
  • Very coarse facial features

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; XL = X-linked

1.

Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

Other conditions/disorders of unknown genetic cause to consider in the differential diagnosis are listed in Table 3b.

Table 3b.

PUF60-Related Disorders: Conditions/Disorders of Unknown Genetic Cause of Interest in the Differential Diagnosis

DisorderFeatures Similar to PUF60-Related DisordersFeatures Distinct from PUF60-Related Disorders
VACTERL association (OMIM 192350)
  • Vertebral anomalies
  • Congenital heart defects
  • Kidney anomalies
Anal atresia
Dubowitz syndrome 1
  • Short stature
  • Microcephaly
  • Craniofacial features
  • Eczema, skin issues
  • Characteristic triangular face

Management

No clinical practice guidelines for PUF60-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with PUF60-related disorders.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a PUF60-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

PUF60-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Constitutional Eval by pediatricianAssess overall well-being.
Neurologic Neurologic eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
Dysarthria Speech therapy services & language support servicesTo evaluate & support development of speech & language abilities
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Neurobehavioral/
Psychiatric 		Neuropsychiatric evalFor persons age >12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD
Orthopedic Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Contractures, pes equinovarus, & kyphoscoliosis
  • Mobility, ADL, & need for adaptive devices
  • Hip ultrasound to assess for congenital hip dysplasia
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eyes Ophthalmologic evalTo assess for reduced vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus, & more complex findings (e.g., cataract) that may require referral for subspecialty care &/or low vision services
Hearing Audiologic evalTo assess for hearing loss
Mouth By pediatrician; referral to dentist specialist as needed
  • Assess for dental issues.
  • Assess for palatal malformations (e.g., high-arched palate, cleft lip & palate, & micrognathia).
Cardiovascular Cardiovascular evalTo assess for cardiac malformations
Respiratory By pediatric pulmonologistTo evaluate for aspiration risk & need for treatment of respiratory infections
CAKUT Abdominal ultrasound exam
  • For those w/kidney anomalies: assess kidney function & if kidney abnormalities are identified, refer to a nephrologist.
  • For those w/urinary tract anomalies: refer to a urologist.
Genital anomalies By pediatrician; referral to pediatric surgeon or urologist as neededTo assess for cryptorchidism & possible other genital anomalies
Skin Dermatologic evalIf needed; to assess for eczema, keratosis, & possible complications
Endocrine By pediatrician; referral to endocrinologist as neededTo assess for short stature & pubertal development
Immunology By pediatrician; referral to immunologist as needed
  • To assess for manifestations of possible immunodeficiency incl recurrent infections or inflammatory bowel disorder
  • If needed, assess blood count, lymphocyte subsets, & immunoglobulins.
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PUF60-related disorders to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

For individuals with severe, clinically defined classic Verheij syndrome, a clinical ethics consultation may be considered to assess health care decisions in the context of the best interest of the child and the values and preferences of the family.

Treatment of Manifestations

There is no cure for PUF60-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5). This may include multidisciplinary care by specialists in clinical genetics and pediatric specialists and allied health professionals in neurology, audiology, ophthalmology, development (including physical therapy and speech-language pathology), feeding, cardiology, pulmonology, gastroenterology, immunology, endocrinology, nephrology, urology, and orthopedics.

Considering the complexities of medical problems in some severely affected individuals, input from palliative care and medical ethics may also be beneficial, particularly when decisions about invasive procedures are made.

To date, the use of growth hormone therapy has been considered a treatment option for short stature in four individuals (none of whom had significant growth hormone deficiency based on standard laboratory testing) who showed continuous growth velocity reported over a course of up to three years [Grimes et al 2023, Baum et al 2024, Sivasubramanian & Ayyavoo 2024]. There is one report of side effects that resulted in discontinuation of growth hormone therapy due to development of idiopathic intracranial hypertension [Sivasubramanian & Ayyavoo 2024].

Table 5.

PUF60-Related Disorders: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay / Intellectual disability / Neurobehavioral issues See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Poor weight gain /
Failure to thrive
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Eyes Per ophthalmologistFor refractive errors, strabismus
Per ophthalmic subspecialistFor more complex findings (e.g., cataract)
Low vision services
  • Children: through early intervention programs &/or school district
  • Adults: low vision clinic &/or community vision services / OT / mobility services
Sensorineural hearing loss Hearing aids may be helpful per otolaryngologistCommunity hearing services through early intervention or school district
Bowel dysfunction ConstipationStool softeners, prokinetics, osmotic agents, or laxatives as needed
Cardiac involvement Per treating cardiologist
Pulmonary function During chest infections, rigorous antibiotic therapy & chest PTPotentially ICU treatment & ventilation if needed
Kidney function Per treating nephrologist
Urinary tract anomalies Per treating urologist
Immunologic involvement Per treating immunologist
Dermatologic involvement Per primary care physician
  • Avoid excessive sun exposure.
  • Use protective clothing & sunscreen when appropriate.
  • Consider treatment for eczema.
Musculoskeletal PT/OTReferral to orthopedic surgeon as indicated for talipes equinovarus & kyphoscoliosis
Transition to adult care Develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~10 yrs
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports.

ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices only if needed for more severe disease presentations within the spectrum (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended and reflect information in the literature.

Table 6.

PUF60-Related Disorders: Recommended Surveillance

System/ConcernEvaluationFrequency
Developmental delay / Intellectual disability Monitor developmental progress & educational needs.At each visit
Neurobehavioral/
Psychiatric 		Assessment for anxiety, ADHD, ASD, aggression, & self-injury
Neurologic Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as seizures, changes in tone, & movement disorders.
  • Perform EEG or brain MRI if clinically needed.
Per treating clinician
Growth & weight gain
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Ophthalmologic involvement Ophthalmologic eval for cataractsPer treating ophthalmologist(s)
Low vision servicesPer treating low vision specialists
Sensorineural
hearing loss 		Brain stem evoked responses in case of suspected hearing impairmentAs SNHL may not be present at birth, hearing needs to be assessed at scheduled intervals per treating audiologist
Gastrointestinal Monitor for constipation & bowel dysfunction.At each visit
Musculoskeletal
  • Physical medicine & OT/PT assessment of mobility & self-help skills
  • Assess for scoliosis &/or foot deformities after birth & if suspected later in life.
  • Spine radiographs as indicated
Per treating clinician
Cardiovascular Per treating cardiologistPer treating cardiologist
Respiratory Monitor for aspiration & pulmonary complications per treating clinician.At each visit
CAKUT For those w/known kidney involvement: per treating nephrologistPer treating nephrologist
For those w/o known kidney involvement: evaluate kidney function.Per primary care physician
Immunology Full blood counts & specific immunologic investigations if there are clinical concerns.Per treating immunology specialist
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PUF60-related disorders are autosomal dominant disorders typically caused by a de novo genetic alteration (either a pathogenic variant in PUF60 or a contiguous gene deletion of 8q24.3 including PUF60).

Risk to Family Members

Parents of a proband

  • To date, most probands reported with a PUF60-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo genetic alteration.
  • Rarely, individuals diagnosed with a PUF60-related disorder have the disorder as the result of a genetic alteration inherited from a parent.
  • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
  • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • The proband has de novo genetic alteration.
    • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only.
      * A parent with somatic and gonadal mosaicism for a genetic alteration involving PUF60 may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with a PUF60-related disorder has a 50% chance of inheriting the causative genetic alteration.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PUF60 pathogenic variant or contiguous gene deletion involving PUF60, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals and individuals with a PUF60-related disorder.

Prenatal Testing and Preimplantation Genetic Testing

Once the genetic alteration involving PUF60 has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PUF60-Related Disorders: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
PUF608q24​.3Poly(U)-binding-splicing factor PUF60PUF60PUF60

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PUF60-Related Disorders (View All in OMIM)

604819POLY-U-BINDING SPLICING FACTOR, 60-KD; PUF60
615583VERHEIJ SYNDROME; VRJS

Molecular Pathogenesis

PUF60 encodes the poly(U)-binding-splicing factor PUF60 (PUF60), a small protein that is essential in the early stage of spliceosome assembly. PUF60 binds polyuridine (U) tracts and promotes the association of the precursor transcripts with the U2 small nuclear ribonucleoprotein complex. PUF60 contains two central RNA recognition motifs (RRM1 and RRM2) and a C-terminal U2AF-homology motif (UHM; alternatively termed RRM3) [Královičová et al 2018]. PUF60 also seems to play a role in cellular migration, proliferation, and viability [Hastings et al 2007, Sun et al 2019, Xu et al 2023, Baum et al 2024].

Recent work has begun to elucidate the molecular pathomechanisms underlying PUF60-related disorders, demonstrating that partial loss of the PUF60 ortholog rnp-6 in the model organism Caenorhabditis elegans induces widespread splicing defects that perturb one-carbon and phospholipid metabolism, notably the methionine–S-adenosylmethionine–phosphatidylcholine axis (see bioRxiv; pre-peer review). These metabolic imbalances activate the integrated stress response and impair mTORC1 signaling, causing developmental delay reminiscent of human PUF60-related disorders. The mTOR downregulation has previously been reported in cells and worms as well [Huang et al 2022]. Aberrant intron retention in the nhr-114/HNF4 transcription factor was identified as a key mechanistic driver of the metabolic defect.

Mechanism of disease causation. Preliminary data to date suggest that the mechanism of disease causation is loss of function.

Chapter Notes

Author Notes

Emily Baum and Hormos Dafsari are actively involved in clinical research regarding individuals with PUF60-related disorders and would be willing to communicate with persons regarding the diagnosis of PUF60-related disorders or other considerations.

Emily Baum, Jonathan Kölschbach, Wenming Huang, Adam Antebi, and Hormos Dafsari are actively involved in basic scientific research on PUF60-related disorders and disorders of the spliceosome (splicosomopathies), as well as in the restoration of methylation potential and reactivation of mTORC1 signaling in human cells.

Contact Hormos Dafsari to inquire about review of PUF60 variants of uncertain significance.

Acknowledgments

EB was supported by the Cologne Clinician Scientist Program / Medical Faculty / University of Cologne.

Revision History

  • 28 July 2026 (bp) Review posted live
  • 26 January 2026 (hsd) Original submission

References

Literature Cited

  • Abdin D, Rump A, Tzschach A, Sarnow K, Schröck E, Hackmann K, Di Donato N. PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome. Eur J Med Genet. 2019;62:103587. [PubMed: 30472487]
  • Alkhunaizi E, Braverman N. Clinical characterization of a PUF60 variant in a patient with Dubowitz-like syndrome. Am J Med Genet A. 2019;179:130-33. [PubMed: 30569551]
  • Baum E, Huang W, Vincent-Delorme C, Brunelle P, Antebi A, Dafsari HS. Novel genetic and phenotypic expansion in ameliorated PUF60-related disorders. Int J Mol Sci. 2024;25:2053. [PMC free article: PMC10889399] [PubMed: 38396730]
  • Dauber A, Golzio C, Guenot C, Jodelka FM, Kibaek M, Kjaergaard S, Leheup B, Martinet D, Nowaczyk MJ, Rosenfeld JA, Zeesman S, Zunich J, Beckmann JS, Hirschhorn JN, Hastings ML, Jacquemont S, Katsanis N. SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant. Am J Hum Genet. 2013;93:798-811. [PMC free article: PMC3824129] [PubMed: 24140112]
  • El Chehadeh S, Kerstjens-Frederikse WS, Thevenon J, Kuentz P, Bruel AL, Thauvin-Robinet C, Bensignor C, Dollfus H, Laugel V, Riviere JB, Duffourd Y, Bonnet C, Robert MP, Isaiko R, Straub M, Creuzot-Garcher C, Calvas P, Chassaing N, Loeys B, Reyniers E, Vandeweyer G, Kooy F, Hancarova M, Havlovicova M, Prchalova D, Sedlacek Z, Gilissen C, Pfundt R, Wassink-Ruiter JSK, Faivre L. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature. Eur J Hum Genet. 2016;25:43-51. [PMC free article: PMC5159768] [PubMed: 27804958]
  • Fennell AP, Baxter AE, Berkovic SF, Ellaway CJ, Forwood C, Hildebrand MS, Kumble S, McKeown C, Mowat D, Poke G, Rajagopalan S, Regan BM, Scheffer IE, Stark Z, Stutterd CA, Tan TY, Wilkins EJ, Yeung A, Hunter MF. The diverse pleiotropic effects of spliceosomal protein PUF60: a case series of Verheij syndrome. Am J Med Genet A. 2022;188:3432-47. [PubMed: 36367278]
  • Graziano C, Gusson E, Severi G, Isidori F, Wischmeijer A, Brugnara M, Seri M, Rossi C. A de novo PUF60 mutation in a child with a syndromic form of coloboma and persistent fetal vasculature. Ophthalmic Genet. 2017;38:590-2. [PubMed: 28471317]
  • Grimes H, Ansari M, Ashraf T, Cueto-González AM, Calder A, Day M, Fernandez Alvarez P, Foster A, Lahiri N, Repetto GM, Scurr I, Varghese V, Low KJ. PUF60-related developmental disorder: a case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants. Am J Med Genet A. 2023;191:2610-22. [PubMed: 37303278]
  • Hastings ML, Allemand E, Duelli DM, Myers MP, Krainer AR. Control of pre-mRNA splicing by the general splicing factors PUF60 and U2AF(65). PLoS One. 2007;2:e538. [PMC free article: PMC1888729] [PubMed: 17579712]
  • Hoogenboom A, Falix FA, van der Laan L, Kerkhof J, Alders M, Sadikovic B, van Haelst MM. Novel PUF60 variant suggesting an interaction between Verheij and Cornelia de Lange syndrome: phenotype description and review of the literature. Eur J Hum Genet. 2024;32:435-9. [PMC free article: PMC10999433] [PubMed: 38273166]
  • Huang W, Kew C, Fernandes SA, Lohrke A, Han L, Demetriades C, Antebi A. Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity. Nat Aging. 2022;2:796-808. [PMC free article: PMC10154236] [PubMed: 37118503]
  • Kursat YD, Sezginer Guler H, Zhuri D, Gurkan H, Yalcintepe S. Clinical and genetic aspects of Verheij syndrome in two cases. Mol Syndromol. 2026;17:59-66. [PMC free article: PMC12055013] [PubMed: 40881056]
  • Low KJ, Ansari M, Abou Jamra R, Clarke A, El Chehadeh S, FitzPatrick DR, Greenslade M, Henderson A, Hurst J, Keller K, Kuentz P, Prescott T, Roessler F, Selmer KK, Schneider MC, Stewart F, Tatton-Brown K, Thevenon J, Vigeland MD, Vogt J, Willems M, Zonana J, Study DD, Smithson SF. PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features. Eur J Hum Genet. 2017;25:552-9. [PMC free article: PMC5392357] [PubMed: 28327570]
  • Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM, Directors ABo. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
  • Miao M, Wang J, Guo C, Su X, Sun L, Lu S. Identification of a novel de novo PUF60 variant causing Verheij syndrome in a fetus. Gene. 2024;897:148092. [PubMed: 38110042]
  • Moccia A, Srivastava A, Skidmore JM, Bernat JA, Wheeler M, Chong JX, Nickerson D, Bamshad M, Hefner MA, Martin DM, Bielas SL. Genetic analysis of CHARGE syndrome identifies overlapping molecular biology. Genet Med. 2018;20:1022-9. [PMC free article: PMC6034995] [PubMed: 29300383]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Rodan LH, Stoler J, Chen E, Geleske T; Council on Genetics. Genetic evaluation of the child with intellectual disability or global developmental delay: clinical report. Pediatrics. 2025;156:e2025072219. [PubMed: 40545261]
  • Santos-Simarro F, Vallespin E, Del Pozo A, Ibañez K, Silla JC, Fernandez L, Nevado J, González-Pecellín H, Montaño VEF, Martin R, Alba Valdivia LI, García-Miñaúr S, Lapunzina P, Palomares-Bralo M. Eye coloboma and complex cardiac malformations belong to the clinical spectrum of PUF60 variants. Clin Genet. 2017;92:350-1. [PubMed: 28074499]
  • Sivasubramanian D, Ayyavoo A. A case report of Verheij syndrome. Cureus. 2024;16:e66692. [PMC free article: PMC11390954] [PubMed: 39268253]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Sun D, Lei W, Hou X, Li H, Ni W. PUF60 accelerates the progression of breast cancer through down-regulation of PTEN expression. Cancer Manag Res. 2019;11:821-30. [PMC free article: PMC6340502] [PubMed: 30697074]
  • Toader DO, Ursu R, Bacalbasa N, Cretoiu D, Pop LG, Balescu I, Gherghiceanu F, Furtunescu F, Radavoi D, Radoi V. Identification of a new variant of PUF60 gene: case presentation and literature review. Cancer Diagn Progn. 2021;1:213-9. [PMC free article: PMC8962785] [PubMed: 35399315]
  • Verheij JB, de Munnik SA, Dijkhuizen T, de Leeuw N, Olde Weghuis D, van den Hoek GJ, Rijlaarsdam RS, Thomasse YE, Dikkers FG, Marcelis CL, van Ravenswaaij-Arts CM. An 8.35 Mb overlapping interstitial deletion of 8q24 in two patients with coloboma, congenital heart defect, limb abnormalities, psychomotor retardation and convulsions. Eur J Med Genet. 2009;52:353-7. [PubMed: 19464398]
  • Xu N, Ren Y, Bao Y, Shen X, Kang J, Wang N, Wang Z, Han X, Li Z, Zuo J, Wei GH, Wang Z, Zong WX, Liu W, Xie G, Wang Y. PUF60 promotes cell cycle and lung cancer progression by regulating alternative splicing of CDC25C. Cell Rep. 2023;42:113041. [PMC free article: PMC13034450] [PubMed: 37682709]
  • Zemet R, Van den Veyver IB, Stankiewicz P. Parental mosaicism for apparent de novo genetic variants: scope, detection, and counseling challenges. Prenat Diagn. 2022;42:811-821. [PMC free article: PMC9995893] [PubMed: 35394072]
  • Zhao JJ, Halvardson J, Zander CS, Zaghlool A, Georgii-Hemming P, Månsson E, Brandberg G, Sävmarker HE, Frykholm C, Kuchinskaya E, Thuresson AC, Feuk L. Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. Am J Med Genet B Neuropsychiatr Genet. 2018;177:10-20. [PMC free article: PMC5765476] [PubMed: 28990276]
Copyright © 1993-2026, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. Test.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (https://www.genereviews.org) and copyright (© 1993-2026 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: addmast@wu.edu

Bookshelf ID: NBK623826PMID: 42520151
GeneReviews by Title

Views

In this GeneReview

Bulk Download

GeneReviews Links

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

ClearTurn OffTurn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...