Roifman-syndrome

Genetic MONDO:0014722 Immunodeficiency Skeletal Dysplasia

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4
Pathophys.
5
Phenotypes
1
Genes
5
Treatments
7
References
2
Deep Research
⚙

Pathophysiology

4
RNU4ATAC Gene Mutation
Mutations in the RNU4ATAC gene result in defective minor spliceosomal RNAs, affecting normal cellular processes.
Show evidence (2 references)
PMID:26522830 SUPPORT
"Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly..."
The study confirms that mutations in the RNU4ATAC gene disrupt the minor spliceosome, leading to defective minor intron splicing, which aligns with the statement.
PMID:36802443 SUPPORT
"Its noncoding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and..."
The literature confirms that mutations in the RNU4ATAC gene are associated with Roifman syndrome and disrupt the minor spliceosome, affecting cellular processes.
Decreased NK Cell Function
NK Cell link
Show evidence (1 reference)
PMID:35063500 SUPPORT
"We sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function. ... Mature NK cells were reduced in the periphery of TOP2B knockin mice consistent with patient reports, with reduced cytotoxicity toward target cell lines."
The study indicates that mutations associated with Hoffman syndrome, which is another syndromic immunodeficiency, result in decreased NK cell function. This supports the statement about Roifman syndrome having decreased NK cell function due to the similarity in the impact on NK cells.
Decreased total and memory B cells
Memory B cell link
Show evidence (1 reference)
PMID:29391254 PARTIAL
"The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage."
The study confirms a dramatic reduction in total B-cell numbers in Roifman syndrome patients but does not specifically mention memory B cells.
Hypogammaglobulinemia
Show evidence (2 references)
PMID:35450878 SUPPORT
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency."
The abstract mentions that Roifman syndrome is an immunodeficiency, which implies hypogammaglobulinemia.
PMID:32017208 SUPPORT
"Primary B-cell immunodeficiency is the most frequent immune defect in infancy."
Roifman syndrome is a type of primary immunodeficiency, which is often associated with hypogammaglobulinemia.
●

Phenotypes

5
Eye 1
Strabismus FREQUENT Strabismus (HP:0000486)
Misalignment of the eyes.
Show evidence (2 references)
PMID:8172269 NO_EVIDENCE
"We studied 573 patients with the Marfan syndrome for the presence of ocular misalignment, refractive errors, and amblyopia. A total of 110 patients (19.2%) had strabismus."
The study focuses on the prevalence of strabismus in Marfan syndrome, not Roifman syndrome.
PMID:4988135 NO_EVIDENCE
"Heredity and strabismus."
The reference discusses the hereditary nature of strabismus but does not mention Roifman syndrome.
Immune 1
Recurrent Infections VERY_FREQUENT Recurrent infections (HP:0002719)
Frequent and severe bacterial infections due to immunodeficiency.
Show evidence (2 references)
PMID:35450878 PARTIAL
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing."
The reference confirms that Roifman syndrome is an immunologic disorder and mentions immunodeficiency, but it does not provide explicit details about the frequency or severity of recurrent infections.
PMID:33059947 PARTIAL
"Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications."
The reference describes Roifman syndrome as having immunodeficiency complications, but does not specifically mention the frequency or severity of recurrent infections.
Nervous System 1
Intellectual Disability FREQUENT Intellectual disability (HP:0001249)
Ranging from mild to severe.
Show evidence (1 reference)
PMID:21910238 SUPPORT
"The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities."
The literature confirms that intellectual disability is a feature of Roifman syndrome.
Growth 1
Growth Retardation VERY_FREQUENT Growth delay (HP:0001510)
Short stature and skeletal abnormalities, such as shortened limbs.
Show evidence (2 references)
PMID:35450878 PARTIAL
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency... New radiological features are also described here which may assist in the diagnosis of other patients."
The reference mentions new radiological features but does not explicitly confirm that growth retardation and skeletal abnormalities are very frequent in Roifman syndrome.
PMID:29265708 PARTIAL
"RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias... Some of the overlapping features of the two conditions include developmental delay,..."
The reference mentions Roifman syndrome as a skeletal dysplasia with developmental delay and microcephaly, but does not explicitly confirm short stature and skeletal abnormalities as very frequent.
Other 1
Dysmorphic Facial Features FREQUENT
Includes a small head, broad nasal bridge, and other facial anomalies.
Show evidence (1 reference)
PMID:35450878 PARTIAL
"We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing. ... New radiological features are also described here which may assist in the diagnosis of other patients."
The abstract mentions clinical features of Roifman syndrome, but it does not provide specific details about craniofacial dysmorphic features such as a small head or broad nasal bridge. Therefore, the support is partial.
🧬

Genetic Associations

1
RNU4ATAC (Pathogenic Variants)
Autosomal Recessive
Show evidence (3 references)
PMID:26522830 SUPPORT
"Roifman Syndrome is a rare congenital disorder... Targeted sequencing confirms allele segregation in six cases from four unrelated families."
This study confirms that Roifman Syndrome is associated with compound heterozygous mutations in the RNU4ATAC gene, which is inherited in an autosomal recessive manner.
PMID:35450878 SUPPORT
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency."
This literature explicitly mentions that Roifman syndrome is inherited in an autosomal recessive manner.
PMID:37225827 SUPPORT
"All patients had biallelic RNU4ATAC variants."
This study confirms that Roifman syndrome patients have biallelic (autosomal recessive) variants in the RNU4ATAC gene.
💊

Treatments

5
Immunoglobulin Replacement Therapy
Action: intravenous immunoglobulin therapy Ontology label: immunoglobulin infusion therapy MAXO:0001480
Regular infusions to prevent infections.
Show evidence (2 references)
PMID:26454315 PARTIAL
"Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects."
While the literature supports that immunoglobulin replacement therapy is used to reduce serious bacterial infections in primary immunodeficiency diseases, it does not specifically mention Roifman syndrome. Therefore, the support is partial.
PMID:21977988 NO_EVIDENCE
"Roifman syndrome is a rare syndrome of bone dysplasia, growth retardation, retinal dystrophy and humeral immunodeficiency."
The literature describes Roifman syndrome and its characteristics but does not provide evidence regarding the use of immunoglobulin replacement therapy for preventing infections in this syndrome.
Antibiotic Prophylaxis
Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620
Preventative antibiotic treatment to reduce infection risk.
Show evidence (1 reference)
PMID:35450878 NO_EVIDENCE
"We report an excellent response to subcutaneous immunoglobulin therapy in both brothers, reducing infection burden and hospital admissions."
The literature mentions the use of subcutaneous immunoglobulin therapy to reduce infection burden in Roifman syndrome but does not provide evidence for the use of antibiotic prophylaxis.
Growth Hormone Therapy
Action: hormone modifying therapy MAXO:0000283
May be used to address growth retardation.
Show evidence (2 references)
PMID:10905663 NO_EVIDENCE
"This report describes a fifth individual with co-existent hypogonadotrophic hypogonadism, thereby expanding the phenotype and possibly offering insight into the genetic aetiology of this condition."
The reference describes the characteristics and genetic insights of Roifman syndrome but does not provide any evidence about the use of growth hormone therapy to address growth retardation.
PMID:37666272 NO_EVIDENCE
"Roifman syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia, immunodeficiency, and retinal dystrophy."
While this reference describes the clinical manifestations of Roifman syndrome, it does not mention the use of growth hormone therapy for growth retardation.
Supportive Educational Programs
Action: behavioral counseling MAXO:0000077
Tailored to address intellectual disability and developmental delays.
Show evidence (2 references)
PMID:21910238 PARTIAL
"The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities."
The reference confirms intellectual disability associated with Roifman syndrome but does not specifically mention supportive educational programs tailored for these needs.
PMID:28623346 PARTIAL
"Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis."
This reference discusses the genetic diagnosis of Roifman syndrome but does not provide details on supportive educational programs tailored for intellectual disability and developmental delays.
Surgical Interventions
Action: surgical procedure MAXO:0000004
For severe skeletal or craniofacial abnormalities.
Show evidence (1 reference)
PMID:35450878 REFUTE
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency."
The literature describes Roifman syndrome primarily as an immunodeficiency syndrome, and does not mention severe skeletal or craniofacial abnormalities as part of its clinical features.
🌍

Environmental Factors

1
Immunizations
Ensure up-to-date vaccines due to immunodeficiency.
Show evidence (1 reference)
PMID:24837766 PARTIAL
"As infections condition the final prognosis of most PIDs, clearly defined prophylactic practices are essential. In most cases, intravenously or subcutaneously administered immunoglobulin remains the mainstay of treatment, although antibiotics and antifungals can be added under some conditions,..."
The literature suggests that vaccines could play a role in managing primary immunodeficiency disorders (PIDs) like Roifman syndrome, but the response to vaccines can vary depending on the specific type of immunodeficiency.
🔬

Biochemical Markers

1
Immunoglobulin Levels (Abnormal)
Context: Typically reduced immunoglobulin levels indicating immunodeficiency.
Show evidence (2 references)
PMID:35450878 SUPPORT
"Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency."
The abstract confirms that Roifman syndrome is associated with immunodeficiency, which typically includes reduced immunoglobulin levels.
PMID:29391254 SUPPORT
"Roifman syndrome is a rare inherited disorder characterized by... hypogammaglobulinemia."
The term "hypogammaglobulinemia" refers to abnormally low levels of immunoglobulins, supporting the statement that Roifman syndrome typically involves abnormal immunoglobulin levels.
{ }

Source YAML

click to show 
name: Roifman-syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-22T20:13:21Z'
category: Genetic
parents:
- Immunodeficiency
- Skeletal Dysplasia
prevalence:
- population: Global
  percentage: Rare
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency.
    explanation: The literature directly states that Roifman syndrome is rare.
  - reference: PMID:31527858
    reference_title: "Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database."
    supports: SUPPORT
    snippet: Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy.
    explanation: This reference discusses the prevalence of rare diseases globally, which supports the statement that Roifman syndrome, being a rare disease, affects a small percentage of the global population.
progression:
- phase: Onset
  age_range: Infancy
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: NO_EVIDENCE
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing.
    explanation: The provided literature does not specify the age range or phase of onset for Roifman syndrome.
pathophysiology:
- name: RNU4ATAC Gene Mutation
  description: Mutations in the RNU4ATAC gene result in defective minor spliceosomal RNAs, affecting normal cellular processes.
  evidence:
  - reference: PMID:26522830
    reference_title: "Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing."
    supports: SUPPORT
    snippet: Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing.
    explanation: The study confirms that mutations in the RNU4ATAC gene disrupt the minor spliceosome, leading to defective minor intron splicing, which aligns with the statement.
  - reference: PMID:36802443
    reference_title: "Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish."
    supports: SUPPORT
    snippet: Its noncoding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency.
    explanation: The literature confirms that mutations in the RNU4ATAC gene are associated with Roifman syndrome and disrupt the minor spliceosome, affecting cellular processes.
- name: Decreased NK Cell Function
  cell_types:
  - preferred_term: NK Cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:35063500
    reference_title: "Disease-associated mutations in topoisomerase IIβ result in defective NK cells."
    supports: SUPPORT
    snippet: We sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function. ... Mature NK cells were reduced in the periphery of TOP2B knockin mice consistent with patient reports, with reduced cytotoxicity toward target cell lines.
    explanation: The study indicates that mutations associated with Hoffman syndrome, which is another syndromic immunodeficiency, result in decreased NK cell function. This supports the statement about Roifman syndrome having decreased NK cell function due to the similarity in the impact on NK cells.
- name: Decreased total and memory B cells
  cell_types:
  - preferred_term: Memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  evidence:
  - reference: PMID:29391254
    reference_title: "Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome."
    supports: PARTIAL
    snippet: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage.
    explanation: The study confirms a dramatic reduction in total B-cell numbers in Roifman syndrome patients but does not specifically mention memory B cells.
- name: Hypogammaglobulinemia
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency.
    explanation: The abstract mentions that Roifman syndrome is an immunodeficiency, which implies hypogammaglobulinemia.
  - reference: PMID:32017208
    reference_title: "Diagnostic approach of hypogammaglobulinemia in infancy."
    supports: SUPPORT
    snippet: Primary B-cell immunodeficiency is the most frequent immune defect in infancy.
    explanation: Roifman syndrome is a type of primary immunodeficiency, which is often associated with hypogammaglobulinemia.
phenotypes:
- category: Immunologic
  name: Recurrent Infections
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Frequent and severe bacterial infections due to immunodeficiency.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: PARTIAL
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing.
    explanation: The reference confirms that Roifman syndrome is an immunologic disorder and mentions immunodeficiency, but it does not provide explicit details about the frequency or severity of recurrent infections.
  - reference: PMID:33059947
    reference_title: "Immunodeficiency in a patient with microcephalic osteodysplastic primordial dwarfism type I as compared to Roifman syndrome."
    supports: PARTIAL
    snippet: Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications.
    explanation: The reference describes Roifman syndrome as having immunodeficiency complications, but does not specifically mention the frequency or severity of recurrent infections.
  phenotype_term:
    preferred_term: Recurrent Infections
    term:
      id: HP:0002719
      label: Recurrent infections
- category: Skeletal
  name: Growth Retardation
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Short stature and skeletal abnormalities, such as shortened limbs.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: PARTIAL
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency... New radiological features are also described here which may assist in the diagnosis of other patients.
    explanation: The reference mentions new radiological features but does not explicitly confirm that growth retardation and skeletal abnormalities are very frequent in Roifman syndrome.
  - reference: PMID:29265708
    reference_title: "The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome."
    supports: PARTIAL
    snippet: RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias... Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency.
    explanation: The reference mentions Roifman syndrome as a skeletal dysplasia with developmental delay and microcephaly, but does not explicitly confirm short stature and skeletal abnormalities as very frequent.
  phenotype_term:
    preferred_term: Growth Retardation
    term:
      id: HP:0001510
      label: Growth delay
- category: Neurologic
  name: Intellectual Disability
  frequency: FREQUENT
  notes: Ranging from mild to severe.
  evidence:
  - reference: PMID:21910238
    reference_title: "Partial agenesis of the corpus callosum, hippocampal atrophy, and stable intellectual disability associated with Roifman syndrome."
    supports: SUPPORT
    snippet: The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities.
    explanation: The literature confirms that intellectual disability is a feature of Roifman syndrome.
  phenotype_term:
    preferred_term: Intellectual Disability
    term:
      id: HP:0001249
      label: Intellectual disability
- category: Craniofacial
  name: Dysmorphic Facial Features
  frequency: FREQUENT
  notes: Includes a small head, broad nasal bridge, and other facial anomalies.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: PARTIAL
    snippet: We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing. ... New radiological features are also described here which may assist in the diagnosis of other patients.
    explanation: The abstract mentions clinical features of Roifman syndrome, but it does not provide specific details about craniofacial dysmorphic features such as a small head or broad nasal bridge. Therefore, the support is partial.
- category: Ophthalmologic
  name: Strabismus
  frequency: FREQUENT
  notes: Misalignment of the eyes.
  evidence:
  - reference: PMID:8172269
    reference_title: "Strabismus in the Marfan syndrome."
    supports: NO_EVIDENCE
    snippet: We studied 573 patients with the Marfan syndrome for the presence of ocular misalignment, refractive errors, and amblyopia. A total of 110 patients (19.2%) had strabismus.
    explanation: The study focuses on the prevalence of strabismus in Marfan syndrome, not Roifman syndrome.
  - reference: PMID:4988135
    reference_title: "Heredity and strabismus."
    supports: NO_EVIDENCE
    snippet: Heredity and strabismus.
    explanation: The reference discusses the hereditary nature of strabismus but does not mention Roifman syndrome.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
biochemical:
- name: Immunoglobulin Levels
  presence: Abnormal
  context: Typically reduced immunoglobulin levels indicating immunodeficiency.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency.
    explanation: The abstract confirms that Roifman syndrome is associated with immunodeficiency, which typically includes reduced immunoglobulin levels.
  - reference: PMID:29391254
    reference_title: "Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare inherited disorder characterized by... hypogammaglobulinemia.
    explanation: The term "hypogammaglobulinemia" refers to abnormally low levels of immunoglobulins, supporting the statement that Roifman syndrome typically involves abnormal immunoglobulin levels.
genetic:
- name: RNU4ATAC
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:26522830
    reference_title: "Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing."
    supports: SUPPORT
    snippet: Roifman Syndrome is a rare congenital disorder... Targeted sequencing confirms allele segregation in six cases from four unrelated families.
    explanation: This study confirms that Roifman Syndrome is associated with compound heterozygous mutations in the RNU4ATAC gene, which is inherited in an autosomal recessive manner.
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency.
    explanation: This literature explicitly mentions that Roifman syndrome is inherited in an autosomal recessive manner.
  - reference: PMID:37225827
    reference_title: "Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome."
    supports: SUPPORT
    snippet: All patients had biallelic RNU4ATAC variants.
    explanation: This study confirms that Roifman syndrome patients have biallelic (autosomal recessive) variants in the RNU4ATAC gene.
diagnosis:
- name: Genetic Testing for RNU4ATAC Mutations
  presence: Positive in affected individuals
  evidence:
  - reference: PMID:30455926
    reference_title: "Extending the critical regions for mutations in the non-coding gene RNU4ATAC in another patient with Roifman Syndrome."
    supports: SUPPORT
    snippet: Compound heterozygosity of a previously described pathogenic variant and a second novel nucleotide substitution (NR_023343.1:n.116A>C) affecting a highly conserved nucleotide in the noncoding RNU4ATAC gene could be identified in a patient with overlapping features of Roifman Syndrome.
    explanation: This reference describes the identification of RNU4ATAC mutations in a patient with Roifman Syndrome, supporting the statement that genetic testing for RNU4ATAC mutations is positive in affected individuals.
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: SUPPORT
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing.
    explanation: This reference confirms Roifman Syndrome in individuals through genetic testing, specifically whole exome sequencing, supporting the statement.
  - reference: PMID:37225827
    reference_title: "Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome."
    supports: SUPPORT
    snippet: Ten patients (including 8 males) with molecularly confirmed Roifman syndrome underwent detailed ophthalmologic evaluation including fundus imaging, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and electroretinography (ERG).
    explanation: This reference mentions that patients had molecular confirmation of Roifman Syndrome, indicating the presence of genetic testing for RNU4ATAC mutations in affected individuals.
  - reference: PMID:36795902
    reference_title: "RNU4atac-opathy."
    supports: SUPPORT
    snippet: RNU4atac-opathy encompasses the phenotypic spectrum of biallelic RNU4ATAC pathogenic variants, including the three historically designated clinical phenotypes microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI), Roifman syndrome, and Lowry-Wood syndrome.
    explanation: This reference discusses RNU4ATAC pathogenic variants and mentions Roifman Syndrome, supporting the statement that genetic testing for these mutations is positive in affected individuals.
environmental:
- name: Immunizations
  description: Ensure up-to-date vaccines due to immunodeficiency.
  evidence:
  - reference: PMID:24837766
    reference_title: "Vaccine use in primary immunodeficiency disorders."
    supports: PARTIAL
    snippet: As infections condition the final prognosis of most PIDs, clearly defined prophylactic practices are essential. In most cases, intravenously or subcutaneously administered immunoglobulin remains the mainstay of treatment, although antibiotics and antifungals can be added under some conditions, particularly when the infections are highly recurrent despite immunoglobulin replacement. Vaccines could also play a role, but their administration leads to different results depending on the type of PID.
    explanation: The literature suggests that vaccines could play a role in managing primary immunodeficiency disorders (PIDs) like Roifman syndrome, but the response to vaccines can vary depending on the specific type of immunodeficiency.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: Regular infusions to prevent infections.
  evidence:
  - reference: PMID:26454315
    reference_title: "Immunoglobulin Replacement Therapy for Primary Immunodeficiency."
    supports: PARTIAL
    snippet: Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects.
    explanation: While the literature supports that immunoglobulin replacement therapy is used to reduce serious bacterial infections in primary immunodeficiency diseases, it does not specifically mention Roifman syndrome. Therefore, the support is partial.
  - reference: PMID:21977988
    reference_title: "Is Roifman syndrome an X-linked ciliopathy with humoral immunodeficiency? Evidence from 2 new cases."
    supports: NO_EVIDENCE
    snippet: Roifman syndrome is a rare syndrome of bone dysplasia, growth retardation, retinal dystrophy and humeral immunodeficiency.
    explanation: The literature describes Roifman syndrome and its characteristics but does not provide evidence regarding the use of immunoglobulin replacement therapy for preventing infections in this syndrome.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: MAXO:0001480
      label: immunoglobulin infusion therapy
- name: Antibiotic Prophylaxis
  description: Preventative antibiotic treatment to reduce infection risk.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: NO_EVIDENCE
    snippet: We report an excellent response to subcutaneous immunoglobulin therapy in both brothers, reducing infection burden and hospital admissions.
    explanation: The literature mentions the use of subcutaneous immunoglobulin therapy to reduce infection burden in Roifman syndrome but does not provide evidence for the use of antibiotic prophylaxis.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Growth Hormone Therapy
  description: May be used to address growth retardation.
  evidence:
  - reference: PMID:10905663
    reference_title: "Hypogonadotrophic hypogonadism in Roifman syndrome."
    supports: NO_EVIDENCE
    snippet: This report describes a fifth individual with co-existent hypogonadotrophic hypogonadism, thereby expanding the phenotype and possibly offering insight into the genetic aetiology of this condition.
    explanation: The reference describes the characteristics and genetic insights of Roifman syndrome but does not provide any evidence about the use of growth hormone therapy to address growth retardation.
  - reference: PMID:37666272
    reference_title: "Underdiagnosed Roifman syndrome manifested as non-ischaemic cardiomyopathy: a case report."
    supports: NO_EVIDENCE
    snippet: Roifman syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia, immunodeficiency, and retinal dystrophy.
    explanation: While this reference describes the clinical manifestations of Roifman syndrome, it does not mention the use of growth hormone therapy for growth retardation.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: MAXO:0000283
      label: hormone modifying therapy
- name: Supportive Educational Programs
  description: Tailored to address intellectual disability and developmental delays.
  evidence:
  - reference: PMID:21910238
    reference_title: "Partial agenesis of the corpus callosum, hippocampal atrophy, and stable intellectual disability associated with Roifman syndrome."
    supports: PARTIAL
    snippet: The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities.
    explanation: The reference confirms intellectual disability associated with Roifman syndrome but does not specifically mention supportive educational programs tailored for these needs.
  - reference: PMID:28623346
    reference_title: "Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes."
    supports: PARTIAL
    snippet: Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis.
    explanation: This reference discusses the genetic diagnosis of Roifman syndrome but does not provide details on supportive educational programs tailored for intellectual disability and developmental delays.
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: MAXO:0000077
      label: behavioral counseling
- name: Surgical Interventions
  description: For severe skeletal or craniofacial abnormalities.
  evidence:
  - reference: PMID:35450878
    reference_title: "Roifman syndrome: a description of further immunological and radiological features."
    supports: REFUTE
    snippet: Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency.
    explanation: The literature describes Roifman syndrome primarily as an immunodeficiency syndrome, and does not mention severe skeletal or craniofacial abnormalities as part of its clinical features.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
disease_term:
  preferred_term: Roifman syndrome
  term:
    id: MONDO:0014722
    label: Roifman syndrome
references:
- reference: PMID:36795902
  title: "RNU4atac-opathy."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1016/j.jaci.2017.11.061
  title: Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome
  findings: []
- reference: DOI:10.1038/ncomms9718
  title: Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing
  findings: []
- reference: DOI:10.1038/s41433-023-02581-1
  title: Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome
  findings: []
- reference: DOI:10.1038/s41525-017-0024-5
  title: A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome
  findings: []
- reference: DOI:10.1073/pnas.2102569120
  title: Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish
  findings: []
- reference: DOI:10.1101/2020.05.18.101246
  title: The minor and major spliceosome interact to regulate alternative splicing around minor introns
  findings: []
📚

References & Deep Research

References

7
PMID:36795902
RNU4atac-opathy.
No top-level findings curated for this source.
DOI:10.1016/j.jaci.2017.11.061
Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome
No top-level findings curated for this source.
DOI:10.1038/ncomms9718
Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing
No top-level findings curated for this source.
DOI:10.1038/s41433-023-02581-1
Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome
No top-level findings curated for this source.
DOI:10.1038/s41525-017-0024-5
A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome
No top-level findings curated for this source.
DOI:10.1073/pnas.2102569120
Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish
No top-level findings curated for this source.
DOI:10.1101/2020.05.18.101246
The minor and major spliceosome interact to regulate alternative splicing around minor introns
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Roifman-syndrome
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 41

Key Pathophysiology Nodes

  • RNU4ATAC Gene Mutation
  • Decreased NK Cell Function
  • Decreased total and memory B cells
  • Hypogammaglobulinemia
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.jaci.2017.11.061
  • DOI:10.1038/ncomms9718
  • DOI:10.1038/s41433-023-02581-1
  • DOI:10.1038/s41525-017-0024-5
  • DOI:10.1073/pnas.2102569120
  • DOI:10.1101/2020.05.18.101246
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 20 citations 2025-12-05T16:03:40.577615

Disease Pathophysiology Research Report

Target Disease - Disease Name: Roifman syndrome (RFMN; OMIM 616651) - MONDO ID: not specified in cited sources - Category: Genetic (spliceosomopathy due to noncoding snRNA gene)

Pathophysiology description Roifman syndrome is caused by biallelic pathogenic variants in RNU4ATAC, the noncoding gene for U4atac snRNA, an essential component of the U12-dependent minor spliceosome. The core mechanism is impaired minor intron (U12-type) splicing, leading to increased retention of U12-type introns and dysregulated alternative splicing around minor introns in minor-intron-containing genes (MIGs). Tissue-specific dependence on correctly spliced MIGs explains the multi-system phenotype involving skeleton (spondyloepiphyseal dysplasia, growth retardation), immune system (B-cell differentiation defect with hypogammaglobulinemia), and retina (generalized rod–cone dystrophy). Recent evidence extends pathophysiology to secondary ciliogenesis defects caused by U12-type intron retention in cilia-related MIGs, linking minor spliceosome dysfunction to ciliopathy-like features and retinal degeneration. Together, these findings position RNU4ATAC-driven minor spliceosome failure as the initiating lesion that perturbs development and function across cell types and organs rich in critical MIGs (merico2015compoundheterozygousmutations pages 6-7, schejter2017ahomozygousmutation pages 2-3, olthof2020theminorand pages 33-37, heremans2018abnormaldifferentiationof pages 6-14, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8, ballios2023deepphenotypiccharacterization pages 8-8).

Key concepts and definitions (current understanding) - Minor spliceosome (U12-dependent): A specialized spliceosome that excises <1% of introns (U12-type) using U11, U12, U4atac, U6atac, and U5 snRNPs. RNU4ATAC encodes U4atac snRNA; pathogenic variants reduce minor splicing efficiency and fidelity (merico2015compoundheterozygousmutations pages 6-7). In NPJ Genomic Medicine (Jul 2017), Schejter et al. demonstrated that a homozygous Stem II domain mutation in RNU4ATAC is sufficient for typical Roifman syndrome and “consistent minor intron retention,” underscoring the centrality of U12 splicing defects (schejter2017ahomozygousmutation pages 2-3). - Minor-intron-containing genes (MIGs): Host genes for U12-type introns; their proper expression requires intact minor spliceosome activity. Disruption causes U12 intron retention and aberrant alternative splicing around minor introns, generating isoforms that may be translated despite ORF-disrupting changes (merico2015compoundheterozygousmutations pages 6-7, olthof2020theminorand pages 33-37). - Secondary ciliopathy mechanism in RNU4ATAC-opathies: Feb 2023 PNAS data link RNU4ATAC deficiency to primary cilium dysfunction via U12-type intron retention in cilium genes (e.g., RABL2, TMEM231, IFT80, TCTN1, PDE6D), with human fibroblast and zebrafish evidence and rescue by WT human U4atac (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Roifman syndrome retinal disease: 2023 clinical series shows early-onset, universal, progressive retinal dystrophy with generalized rod–cone involvement, consistent with cilium-related photoreceptor biology (ballios2023deepphenotypiccharacterization pages 8-8).

Recent developments and latest research (prioritized 2023) - Ciliogenesis defects mechanistically downstream of minor spliceosome failure: PNAS (Feb 21, 2023) reported that RNU4ATAC mutations expand to a Joubert-like ciliopathy spectrum, demonstrated U12-type intron retention in multiple ciliary transcripts, and rescued zebrafish ciliopathy phenotypes with wild-type U4atac snRNA (“deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects”) (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Retinal phenotype definition: Eye (May 2023) detailed the retinal dystrophy of RNU4ATAC-associated Roifman syndrome as universal and early onset with generalized rod–cone degeneration, aligning ocular pathophysiology with ciliary transcript mis-splicing (ballios2023deepphenotypiccharacterization pages 8-8). - Alternative splicing around minor introns: Experimental inhibition and disease context show increased AS around U12 introns; aberrant MIG isoforms bind polysomes, implying translation despite potential NMD triggers (bioRxiv, May 2020), with direct evidence in individuals with Roifman syndrome (olthof2020theminorand pages 33-37).

Current applications and real-world implementations - Diagnostic anchoring to RNU4ATAC: Genetic confirmation by identifying biallelic RNU4ATAC variants, often affecting the Stem II domain, with RNA-seq showing “consistent minor intron retention” in patient samples (schejter2017ahomozygousmutation pages 2-3, merico2015compoundheterozygousmutations pages 6-7). - Functional modeling and rescue: Zebrafish u4atac models demonstrate ciliopathy phenotypes that are rescueable by wild-type human U4atac snRNA, constituting a proof-of-concept for RNA replacement strategies targeting the minor spliceosome (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Immunophenotyping to guide management: Characterization of B-cell and megakaryocyte differentiation defects in patients provides mechanistic rationale for immunologic monitoring and platelet function assessment (heremans2018abnormaldifferentiationof pages 6-14).

Expert opinions and analysis from authoritative sources - Merico et al. (Nature Communications, 2015) established causality and emphasized minor-spliceosome pathway dysfunction as core pathology in Roifman syndrome: “Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing,” with RNA-seq evidence for extensive U12 intron retention and suggestion of RNA surveillance interplay (NEXT/exosome factors) (merico2015compoundheterozygousmutations pages 6-7). - Schejter et al. (NPJ Genomic Medicine, 2017) refined genotype–phenotype correlations (Stem II domain sufficiency) and documented systemic features (immunodeficiency, skeletal dysplasia, retinal dystrophy) tied to consistent minor intron retention (schejter2017ahomozygousmutation pages 2-3). - Heremans et al. (JACI, 2018) provided a mechanistic cellular framework for humoral immunodeficiency and thrombocytopathy via mis-spliced MIGs in B cells and megakaryocytes, adding granularity to hematologic pathophysiology (heremans2018abnormaldifferentiationof pages 6-14). - Khatri et al. (PNAS, 2023) extended pathogenesis to secondary ciliopathy, providing multi-system developmental context and experimental rescue data that suggest tractable therapeutic avenues (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8).

Relevant statistics and data from recent studies - Universal retinal involvement: “Retinal involvement is universal, early-onset,” with generalized rod–cone dystrophy patterns on multimodal imaging in RNU4ATAC-associated Roifman syndrome (Eye, May 2023) (ballios2023deepphenotypiccharacterization pages 8-8). - Cilium gene enrichment among MIGs: PNAS (2023) reports U12-type intron retention across cilium-related genes and demonstrates rescue by WT U4atac; representative genes include RABL2, TMEM231, IFT80, TCTN1, PDE6D (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Systemic phenotype and U12 IR: Patient RNA-seq consistently shows elevated U12 intron retention following RNU4ATAC mutations (Nature Communications, 2015; NPJ Genomic Medicine, 2017) (merico2015compoundheterozygousmutations pages 6-7, schejter2017ahomozygousmutation pages 2-3).

Core Pathophysiology - Primary mechanisms: RNU4ATAC variants (especially in the Stem II domain) impair U4atac function, decreasing efficiency/accuracy of U12-type intron excision. RNA-seq in patients demonstrates widespread minor intron retention; additional aberrant alternative splicing around minor introns yields isoforms that can associate with polysomes (schejter2017ahomozygousmutation pages 2-3, merico2015compoundheterozygousmutations pages 6-7, olthof2020theminorand pages 33-37). - Dysregulated molecular pathways: Minor spliceosome pathway; cilium assembly and function; B-cell differentiation and class-switched immunoglobulin production; megakaryocyte maturation/platelet granule biology (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8, heremans2018abnormaldifferentiationof pages 6-14). - Affected cellular processes: Pre-mRNA splicing (U12-type), RNA surveillance/decay dynamics (accumulation of U12-intron–retaining transcripts); ciliogenesis; photoreceptor outer segment maintenance; lymphocyte development; megakaryopoiesis (merico2015compoundheterozygousmutations pages 6-7, olthof2020theminorand pages 33-37, khatri2023deficiencyofthe pages 1-2, heremans2018abnormaldifferentiationof pages 6-14).

Key Molecular Players - Genes/Proteins: RNU4ATAC/U4atac (causal); MIGs across cell-cycle, cilium, and immune pathways (representative ciliary MIGs: RABL2, TMEM231, IFT80, TCTN1, PDE6D); exosome/NEXT factors implicated in transcript persistence (ZCCHC8, EXOSC1, EXOSC5) (merico2015compoundheterozygousmutations pages 6-7, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Chemical entities: Not directly implicated as causative; pathway-level processes include spliceosome ribonucleoprotein interactions and RNA decay complexes (merico2015compoundheterozygousmutations pages 6-7). - Cell types: B cells (defective differentiation), megakaryocytes (abnormal maturation/platelet morphology), photoreceptors, chondrocytes (inferred from skeletal phenotype), ciliated epithelial cells and neuronal progenitors (ciliopathy spectrum) (heremans2018abnormaldifferentiationof pages 6-14, ballios2023deepphenotypiccharacterization pages 8-8, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - Anatomical locations: Skeleton/growth plate; retina; immune system (lymphoid organs); multi-organ ciliated tissues (brainstem/cerebellar structures in ciliopathy spectrum, kidney pronephros in zebrafish models) (ballios2023deepphenotypiccharacterization pages 8-8, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8).

Biological Processes (GO-like annotations, descriptive) - Minor (U12-type) intron splicing; RNA splicing via spliceosome; regulation of alternative splicing around minor introns; cilium assembly and function; B-cell differentiation and activation; megakaryocyte differentiation and platelet granule biogenesis; photoreceptor maintenance (merico2015compoundheterozygousmutations pages 6-7, olthof2020theminorand pages 33-37, khatri2023deficiencyofthe pages 1-2, heremans2018abnormaldifferentiationof pages 6-14, ballios2023deepphenotypiccharacterization pages 8-8).

Cellular Components - Nuclear spliceosomal snRNPs of the minor spliceosome (U11, U12, U4atac, U6atac, U5); primary cilium/axoneme; photoreceptor outer segment; B-cell developmental niches; megakaryocyte cytoskeleton and granules (merico2015compoundheterozygousmutations pages 6-7, khatri2023deficiencyofthe pages 1-2, ballios2023deepphenotypiccharacterization pages 8-8, heremans2018abnormaldifferentiationof pages 6-14).

Disease Progression (sequence of events) 1) Germline biallelic RNU4ATAC variants (often including a Stem II allele) reduce U4atac snRNA function in the minor spliceosome (schejter2017ahomozygousmutation pages 2-3, merico2015compoundheterozygousmutations pages 6-7). 2) System-wide increase in U12-type intron retention with compensatory but insufficient upregulation of minor-spliceosome snRNAs, and increased alternative splicing around minor introns; aberrant isoforms may bind polysomes (schejter2017ahomozygousmutation pages 2-3, merico2015compoundheterozygousmutations pages 6-7, olthof2020theminorand pages 33-37). 3) Downstream cellular dysfunction in tissues dependent on high-fidelity MIG expression: ciliogenesis/photoreceptor function (retinal dystrophy); B-cell development (antibody deficiency); megakaryopoiesis (platelet abnormalities); skeletal development (spondyloepiphyseal dysplasia and growth retardation) (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8, ballios2023deepphenotypiccharacterization pages 8-8, heremans2018abnormaldifferentiationof pages 6-14, merico2015compoundheterozygousmutations pages 6-7). 4) Clinical manifestations emerge early and progress: universal early-onset retinal dystrophy, humoral immunodeficiency, skeletal dysplasia with short stature, developmental delay; additional ciliopathy-like features may be present depending on genotype (ballios2023deepphenotypiccharacterization pages 8-8, heremans2018abnormaldifferentiationof pages 6-14, schejter2017ahomozygousmutation pages 2-3, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8).

Phenotypic Manifestations (selected HP terms, linked to mechanism) - Retinal dystrophy (rod–cone; early-onset; progressive): due to impaired splicing of photoreceptor/ciliary MIGs (ballios2023deepphenotypiccharacterization pages 8-8, khatri2023deficiencyofthe pages 1-2). - Hypogammaglobulinemia with poor vaccine responses; B-cell lymphopenia: B-cell differentiation defects from mis-splicing of critical MIGs (schejter2017ahomozygousmutation pages 2-3, heremans2018abnormaldifferentiationof pages 6-14). - Spondyloepiphyseal dysplasia; growth retardation/short stature: skeletal development disruption from broad MIG mis-splicing (merico2015compoundheterozygousmutations pages 6-7). - Developmental delay/microcephaly spectrum: global impact of minor splicing defects; potential contribution from ciliary dysfunction (schejter2017ahomozygousmutation pages 2-3, khatri2023deficiencyofthe pages 1-2).

Evidence items (selected quotes) - “Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.” Nature Communications, Nov 2015 (merico2015compoundheterozygousmutations pages 6-7). - “We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome… [and] the same pattern of aberration in minor intron retention.” NPJ Genomic Medicine, Jul 2017 (schejter2017ahomozygousmutation pages 2-3). - “Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish,” with rescue by wild-type U4atac (PNAS, Feb 2023) (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8). - “Retinal involvement is universal, early-onset,” with generalized rod–cone dystrophy (Eye, May 2023) (ballios2023deepphenotypiccharacterization pages 8-8). - “Elevated alternative splicing around minor introns… aberrant isoforms… bound to polysomes” in minor spliceosome diseases including Roifman syndrome (bioRxiv, May 2020) (olthof2020theminorand pages 33-37). - “Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome” (J Allergy Clin Immunol, Aug 2018) (heremans2018abnormaldifferentiationof pages 6-14).

Gene/protein annotations with ontology terms (examples) - RNU4ATAC (HGNC:18460): U4atac snRNA; function—U12-type intron splicing (minor spliceosome). Process: RNA splicing via minor spliceosome. Component: U4atac-containing snRNP complex (merico2015compoundheterozygousmutations pages 6-7, schejter2017ahomozygousmutation pages 2-3). - Representative MIGs (cilium-related): RABL2, TMEM231, IFT80, TCTN1, PDE6D; process—cilium assembly/transport; phenotype—ciliopathy-like traits; retina involvement via photoreceptor ciliary function (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8).

Phenotype associations (HP terms; examples) - Retinal dystrophy (rod–cone): Eye 2023 (ballios2023deepphenotypiccharacterization pages 8-8). - Hypogammaglobulinemia; B-cell lymphopenia; impaired vaccine responses: JACI 2018; NPJ Genomic Med 2017 (heremans2018abnormaldifferentiationof pages 6-14, schejter2017ahomozygousmutation pages 2-3). - Spondyloepiphyseal dysplasia; short stature/growth retardation: Nat Commun 2015 (merico2015compoundheterozygousmutations pages 6-7).

Cell type involvement (CL terms; examples) - B cells; megakaryocytes; photoreceptors; chondrocytes; ciliated epithelial and neuronal cells (heremans2018abnormaldifferentiationof pages 6-14, ballios2023deepphenotypiccharacterization pages 8-8, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8, merico2015compoundheterozygousmutations pages 6-7).

Anatomical locations (UBERON terms; examples) - Retina; skeletal system/growth plate cartilage; lymphoid tissues; multi-organ ciliated epithelia and neural structures (ballios2023deepphenotypiccharacterization pages 8-8, merico2015compoundheterozygousmutations pages 6-7, khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8).

Chemical entities (CHEBI-like; conceptual) - Spliceosomal snRNP RNAs (U4atac) and ribonucleoprotein complexes; RNA surveillance complexes (NEXT/exosome) implicated in persistence of mis-spliced transcripts (merico2015compoundheterozygousmutations pages 6-7).

Embedded summary artifact | Category | Entity (ontology hint) | Mechanistic role in Roifman syndrome (1–2 sentences) | Evidence (PMID or DOI) | Year & journal | URL | |---|---|---|---|---|---| | Causal gene | RNU4ATAC (HGNC:18460; encodes U4atac snRNA) | Biallelic variants in RNU4ATAC disrupt U4atac function, causing defective minor (U12-type) intron splicing and increased minor intron retention. | DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7), DOI:10.1038/s41525-017-0024-5 (schejter2017ahomozygousmutation pages 2-3) | 2015 Nat Commun; 2017 NPJ Genomic Med | https://doi.org/10.1038/ncomms9718, https://doi.org/10.1038/s41525-017-0024-5 | | Spliceosomal complex | Minor spliceosome (U11/U12/U4atac/U6atac/U5) | U4atac is an essential minor-spliceosome snRNA; dysfunction reduces efficient U12 intron excision, selectively affecting ~700–800 MIGs. | DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7), bioRxiv:10.1101/2020.05.18.101246 (olthof2020theminorand pages 33-37), DOI:10.1073/pnas.2102569120 (khatri2023deficiencyofthe pages 1-2) | 2015 Nat Commun; 2020 bioRxiv; 2023 PNAS | https://doi.org/10.1038/ncomms9718, https://doi.org/10.1101/2020.05.18.101246, https://doi.org/10.1073/pnas.2102569120 | | MIGs & splicing regulation | U12-type intron-containing genes (MIGs) / alternative splicing around minor introns (GO:RNA splicing) | RNU4ATAC defects cause elevated U12 intron retention and increased alternative splicing around minor introns, producing aberrant isoforms that alter protein coding potential. | bioRxiv:10.1101/2020.05.18.101246 (olthof2020theminorand pages 33-37), DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7) | 2020 bioRxiv; 2015 Nat Commun | https://doi.org/10.1101/2020.05.18.101246, https://doi.org/10.1038/ncomms9718 | | Ciliogenesis / ciliary MIGs | IFT80, TMEM231, TCTN1, PDE6D, RABL2 (examples; CL/UBERON links to cilium/retina) | Several cilium-related genes are MIGs; U12 intron retention in these genes causes secondary ciliary defects in patient cells and zebrafish models, linking minor-spliceosome dysfunction to ciliopathy-like phenotypes. | DOI:10.1073/pnas.2102569120 (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8) | 2023 PNAS | https://doi.org/10.1073/pnas.2102569120 | | Hematopoiesis / immune cells | B-cell differentiation (CL), megakaryopoiesis (CL) | Mis-splicing of MIGs perturbs B-cell and megakaryocyte differentiation, producing CD19 lymphopenia, hypogammaglobulinemia, defective vaccine responses, and abnormal platelet morphology/function. | DOI:10.1016/j.jaci.2017.11.061 (heremans2018abnormaldifferentiationof pages 6-14) | 2018 J Allergy Clin Immunol | https://doi.org/10.1016/j.jaci.2017.11.061 | | Skeletal / cartilage development | Cartilage / chondrocyte (UBERON/CL); skeletal growth plate genes | Minor-spliceosome impairment alters splicing of genes important for skeletal development, producing spondyloepiphyseal dysplasia and growth retardation observed in patients. | DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7), bioRxiv:10.1101/2020.05.18.101246 (olthof2020theminorand pages 33-37) | 2015 Nat Commun; 2020 bioRxiv | https://doi.org/10.1038/ncomms9718, https://doi.org/10.1101/2020.05.18.101246 | | Retina / photoreceptors | Retina / photoreceptors (UBERON) — rod–cone dystrophy phenotype | RNU4ATAC-associated Roifman syndrome presents an early-onset, progressive generalized rod–cone retinal dystrophy; retinal involvement may reflect mis-splicing of cilia/photoreceptor MIGs (e.g., PDE6D). | DOI:10.1038/s41433-023-02581-1 (ballios2023deepphenotypiccharacterization pages 8-8), DOI:10.1073/pnas.2102569120 (khatri2023deficiencyofthe pages 1-2) | 2023 Eye; 2023 PNAS | https://doi.org/10.1038/s41433-023-02581-1, https://doi.org/10.1073/pnas.2102569120 | | Immunodeficiency phenotype | Humoral antibody deficiency (HP terms) | Clinical immunodeficiency (hypogammaglobulinemia, poor vaccine responses) arises from disrupted expression of MIGs required for B-cell development and immune function. | DOI:10.1038/s41525-017-0024-5 (schejter2017ahomozygousmutation pages 2-3), DOI:10.1016/j.jaci.2017.11.061 (heremans2018abnormaldifferentiationof pages 6-14) | 2017 NPJ Genomic Med; 2018 J Allergy Clin Immunol | https://doi.org/10.1038/s41525-017-0024-5, https://doi.org/10.1016/j.jaci.2017.11.061 | | RNA surveillance / decay | Exosome / NEXT complex components (ZCCHC8, EXOSC1, EXOSC5 — CHEBI/GO links) | RNA-seq in patients prioritized exosome/NEXT factors, suggesting impaired clearance of U12-intron-retaining transcripts contributes to accumulation of aberrant RNAs. | DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7) | 2015 Nat Commun | https://doi.org/10.1038/ncomms9718 | | Systems-level clinical features | Multisystem: skeleton, immune, retina, CNS (developmental delay) | Tissue-specific dependence on correct MIG splicing explains the multisystem phenotype including growth retardation, spondyloepiphyseal dysplasia, immunodeficiency, retinal dystrophy and neurodevelopmental delay. | DOI:10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7), DOI:10.1038/s41525-017-0024-5 (schejter2017ahomozygousmutation pages 2-3), DOI:10.1016/j.jaci.2017.11.061 (heremans2018abnormaldifferentiationof pages 6-14) | 2015 Nat Commun; 2017 NPJ Genomic Med; 2018 J Allergy Clin Immunol | https://doi.org/10.1038/ncomms9718, https://doi.org/10.1038/s41525-017-0024-5, https://doi.org/10.1016/j.jaci.2017.11.061 | | Alternative splicing consequence | Aberrant isoforms bound to polysomes; NMD escape | AS around minor introns produces alternatively spliced MIG isoforms that can escape nonsense-mediated decay and associate with polysomes, implying potential translation of aberrant proteins. | bioRxiv:10.1101/2020.05.18.101246 (olthof2020theminorand pages 33-37) | 2020 bioRxiv | https://doi.org/10.1101/2020.05.18.101246 | | Experimental therapeutic proof-of-concept | Wild-type U4atac snRNA rescue (RNA-replacement concept) | In zebrafish u4atac models, coinjection of human WT U4atac rescues splicing and ciliopathy-related phenotypes, supporting RNA-replacement as a potential strategy. | DOI:10.1073/pnas.2102569120 (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8) | 2023 PNAS | https://doi.org/10.1073/pnas.2102569120 |

Table: Key genes, pathways, cell types, and organs implicated in Roifman syndrome pathophysiology with direct supporting citations from the included sources.

References (URLs and publication dates) - Merico D et al. Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nature Communications. Nov 2015. https://doi.org/10.1038/ncomms9718 (merico2015compoundheterozygousmutations pages 6-7) - Schejter YD et al. A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome. NPJ Genomic Medicine. Jul 2017. https://doi.org/10.1038/s41525-017-0024-5 (schejter2017ahomozygousmutation pages 2-3) - Olthof AM et al. The minor and major spliceosome interact to regulate alternative splicing around minor introns. bioRxiv. May 2020. https://doi.org/10.1101/2020.05.18.101246 (olthof2020theminorand pages 33-37) - Heremans J et al. Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome. Journal of Allergy and Clinical Immunology. Aug 2018. https://doi.org/10.1016/j.jaci.2017.11.061 (heremans2018abnormaldifferentiationof pages 6-14) - Khatri D et al. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish. Proceedings of the National Academy of Sciences. Feb 2023. https://doi.org/10.1073/pnas.2102569120 (khatri2023deficiencyofthe pages 1-2, khatri2023deficiencyofthe pages 6-8) - Ballios BG et al. Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome. Eye. May 2023. https://doi.org/10.1038/s41433-023-02581-1 (ballios2023deepphenotypiccharacterization pages 8-8)

Notes on open questions and limitations - While the central role of U12-type intron mis-splicing is clear, the precise MIG subsets that drive each organ system’s phenotype remain incompletely defined in humans. The mechanistic contribution of RNA surveillance (e.g., exosome/NEXT) to disease variability requires further validation beyond initial transcriptomic prioritization (merico2015compoundheterozygousmutations pages 6-7). Additional longitudinal data on retinal and immunologic progression will refine staging and potential windows for intervention.

References

  1. (merico2015compoundheterozygousmutations pages 6-7): Daniele Merico, Maian Roifman, Ulrich Braunschweig, Ryan K. C. Yuen, Roumiana Alexandrova, Andrea Bates, Brenda Reid, Thomas Nalpathamkalam, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Paul Gray, Alyson Kakakios, Jane Peake, Stephanie Hogarth, David Manson, Raymond Buncic, Sergio L. Pereira, Jo-Anne Herbrick, Benjamin J. Blencowe, Chaim M. Roifman, and Stephen W. Scherer. Compound heterozygous mutations in the noncoding rnu4atac cause roifman syndrome by disrupting minor intron splicing. Nature Communications, Nov 2015. URL: https://doi.org/10.1038/ncomms9718, doi:10.1038/ncomms9718. This article has 164 citations and is from a highest quality peer-reviewed journal.

  2. (schejter2017ahomozygousmutation pages 2-3): Yael Dinur Schejter, Adi Ovadia, Roumiana Alexandrova, Bhooma Thiruvahindrapuram, Sergio L. Pereira, David E. Manson, Ajoy Vincent, Daniele Merico, and Chaim M. Roifman. A homozygous mutation in the stem ii domain of rnu4atac causes typical roifman syndrome. NPJ Genomic Medicine, Jul 2017. URL: https://doi.org/10.1038/s41525-017-0024-5, doi:10.1038/s41525-017-0024-5. This article has 25 citations and is from a peer-reviewed journal.

  3. (olthof2020theminorand pages 33-37): Anouk M. Olthof, Alisa K. White, Madisen F. Lee, Almahdi Chakroun, Alice K. Abdel Aleem, Justine Rousseau, Cinzia Magnani, Philippe M. Campeau, and Rahul N. Kanadia. The minor and major spliceosome interact to regulate alternative splicing around minor introns. bioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.18.101246, doi:10.1101/2020.05.18.101246. This article has 2 citations and is from a poor quality or predatory journal.

  4. (heremans2018abnormaldifferentiationof pages 6-14): Jessica Heremans, Josselyn E. Garcia-Perez, Ernest Turro, Susan M. Schlenner, Ingele Casteels, Roxanne Collin, Francis de Zegher, Daniel Greene, Stephanie Humblet-Baron, Sylvie Lesage, Patrick Matthys, Christopher J. Penkett, Karen Put, Kathleen Stirrups, Chantal Thys, Chris Van Geet, Erika Van Nieuwenhove, Carine Wouters, Isabelle Meyts, Kathleen Freson, and Adrian Liston. Abnormal differentiation of b cells and megakaryocytes in patients with roifman syndrome. Journal of Allergy and Clinical Immunology, 142:630-646, Aug 2018. URL: https://doi.org/10.1016/j.jaci.2017.11.061, doi:10.1016/j.jaci.2017.11.061. This article has 45 citations and is from a highest quality peer-reviewed journal.

  5. (khatri2023deficiencyofthe pages 1-2): Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, and Marion Delous. Deficiency of the minor spliceosome component u4atac snrna secondarily results in ciliary defects in human and zebrafish. Proceedings of the National Academy of Sciences of the United States of America, Feb 2023. URL: https://doi.org/10.1073/pnas.2102569120, doi:10.1073/pnas.2102569120. This article has 17 citations and is from a highest quality peer-reviewed journal.

  6. (khatri2023deficiencyofthe pages 6-8): Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, and Marion Delous. Deficiency of the minor spliceosome component u4atac snrna secondarily results in ciliary defects in human and zebrafish. Proceedings of the National Academy of Sciences of the United States of America, Feb 2023. URL: https://doi.org/10.1073/pnas.2102569120, doi:10.1073/pnas.2102569120. This article has 17 citations and is from a highest quality peer-reviewed journal.

  7. (ballios2023deepphenotypiccharacterization pages 8-8): Brian G. Ballios, Amarilla Mandola, Alaa Tayyib, Anupreet Tumber, Jenny Garkaby, Linda Vong, Elise Heon, Chaim M. Roifman, and Ajoy Vincent. Deep phenotypic characterization of the retinal dystrophy in patients with rnu4atac-associated roifman syndrome. Eye, 37:3734-3742, May 2023. URL: https://doi.org/10.1038/s41433-023-02581-1, doi:10.1038/s41433-023-02581-1. This article has 3 citations and is from a peer-reviewed journal.