Intellectual Disability X-linked Syndromic 35

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Inheritance

1

X-linked recessive inheritance HP:0001419

Affected individuals are hemizygous males. In the pedigrees through which the disorder was defined the variant was maternally transmitted by an unaffected carrier, and skewed X inactivation was documented in carrier females, consistent with causality. Expressivity in males is markedly variable, from intellectual disability with dysmorphism to a severe multisystem phenotype with refractory epilepsy. De novo occurrence has been reported once.

X-linked recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:25316788 SUPPORT Human Clinical

"the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation"

States the X-linked recessive segregation and the skewed X inactivation in carrier females.

PMID:29066376 SUPPORT Human Clinical

"This is the first instance that a de novo mutation in RPL10 has been reported."

Documents that de novo occurrence, while the exception, does happen.

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Discussions and Knowledge Gaps

3

Does the 60S maturation checkpoint failure demonstrated for uL16 in yeast actually occur in cells carrying the MRXS35 alleles?

KNOWLEDGE GAP ul16_maturation_checkpoint_untested_in_syndromic_alleles

Attached to

pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation

The molecular step in this entry's central node - trapping of Nmd3 in the P site and failure to release Tif6 - has been demonstrated for the somatic leukemia allele rpl10-R98S in S. cerevisiae, not for any of the germline syndromic alleles. The MRXS35 alleles have been assayed only at coarser resolution: morphant rescue in zebrafish (p.K78E), transcript and protein level in transfected cells (p.R116Q), and polysome distribution in yeast (p.A64V). No study has measured Nmd3/Tif6 release, pre-60S quality control passage, or subunit joining for a syndromic allele. The chain from the initiating lesion to reduced translational capacity is therefore assembled from a conserved-protein argument rather than from direct measurement in this disease, and the evidence items on those edges are graded INDIRECT for that reason.

Proposed experiments

Late 60S maturation assay across the MRXS35 allelic series

late_60s_maturation_assay_across_mrxs35_alleles

Reconstitute each syndromic RPL10 allele (p.R32L, p.A64V, p.K78E, p.R116Q) alongside p.R98S and wild type, and measure Nmd3 and Tif6 release, pre-60S cytoplasmic quality control passage, and 60S-40S subunit joining.

Would support

pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation

Would refute

pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation

Supporting outcome

Syndromic alleles show retained Nmd3 and Tif6 on cytoplasmic pre-60S particles and reduced subunit joining relative to wild type.

Refuting outcome

Syndromic alleles release Nmd3 and Tif6 normally and join subunits at wild-type rates, indicating the neurodevelopmental alleles act through a mechanism other than the late maturation checkpoint.

Show evidence (1 reference)

PMID:28715419 SUPPORT INDIRECT In Vitro

"Mutations in the ribosomal protein Rpl10 (uL16) can be drivers of T-cell acute lymphoblastic leukemia (T-ALL)."

Establishes the gap: the allele in which this checkpoint defect was characterised is a leukemia driver, not one of the germline syndromic alleles this entry is about.

Does a mammalian model carrying a human MRXS35 allele reproduce the disorder, or is the whole mechanistic account resting on a transient fish knockdown?

HUMAN MODEL MISMATCH no_humanized_knock_in_mammalian_model

Attached to

animal_models#Zebrafish pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain

The only in vivo model of this disorder is transient morpholino knockdown of rpl10 in zebrafish. That model suppresses the gene entirely, whereas every reported patient carries a hemizygous missense allele that still produces protein, so it models absence rather than substitution. Its one allele-specific result is a failed rescue, which shows p.K78E is loss of function but does not show what the mutant protein does. No knock-in mouse or other mammalian model carrying a human MRXS35 allele has been reported, so the cerebellar, retinal, skeletal and craniofacial features have no in vivo model at all, and the developmental timing of the microcephaly - postnatal in patients - cannot be studied in a fish embryo assay. This is a model-fidelity question rather than an absence of evidence, which is why it is filed as HUMAN_MODEL_MISMATCH.

Proposed experiments

Knock-in mouse carrying a human MRXS35 allele

humanized_knock_in_mouse_for_mrxs35_alleles

Generate mice carrying the orthologous p.K78E and p.R32L substitutions and phenotype them for postnatal head growth, cerebellar development, retinal degeneration, skeletal morphology and seizure susceptibility, against the corresponding null allele as a comparator.

Would support

pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain

Would refute

pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain

Supporting outcome

Knock-in mice reproduce postnatal microcephaly with reduced neural progenitor proliferation and increased apoptosis, and the allele-specific retinal and skeletal features track the alleles that carry them in patients.

Refuting outcome

Knock-in mice are unaffected, or show a phenotype only at null-allele dosage, indicating the zebrafish knockdown phenotype reflects gene loss rather than what the human missense alleles do.

Why does p.A64V increase the actively translating ribosome population when a loss-of-function model predicts the opposite?

KNOWLEDGE GAP a64v_increased_translating_ribosomes_paradox

Attached to

pathophysiology#p.A64V Increases the Actively Translating Ribosome Population genetic#RPL10

The dominant mechanistic account of this disorder is loss of function, and two alleles support it. p.A64V does not: in yeast it complements a conditional lethal rpl10 mutation and shifts the polysome profile toward more actively translating ribosomes, yet the two cousins carrying it have intellectual disability, cerebellar hypoplasia and spondyloepiphyseal dysplasia. Either the disorder can arise from opposite directions of translational perturbation, or the yeast polysome readout does not capture the relevant human defect. This matters for interpretation of new missense alleles, which are routinely returned as variants of uncertain significance and adjudicated against a loss-of-function expectation.

Proposed experiments

Human neural cell comparison of p.A64V against loss-of-function alleles

a64v_vs_lof_in_human_neural_progenitors

Introduce p.A64V and a demonstrated loss-of-function allele into isogenic human iPSC-derived neural progenitors and compare ribosome content, bulk translation rate, translational fidelity and the translated transcriptome.

Would support

pathophysiology#Reduced Pool of Translation-Competent 60S Subunits

Would refute

pathophysiology#Reduced Pool of Translation-Competent 60S Subunits

Supporting outcome

p.A64V reduces ribosome content or bulk translation in human neural cells despite the opposite polysome result in yeast, reconciling it with the loss-of-function chain.

Refuting outcome

p.A64V leaves ribosome content and bulk translation intact while altering which transcripts are translated, indicating a qualitative rather than quantitative translational lesion.

Show evidence (1 reference)

PMID:26290468 SUPPORT In Vitro

"The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10."

Documents the observation that creates the gap: a pathogenic allele that nonetheless yields a functional protein, contradicting a uniform loss-of-function account.

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Pathophysiology

8

RPL10 Missense Substitution in uL16

A hemizygous missense substitution alters uL16, the 60S ribosomal subunit protein encoded by RPL10. The syndromic alleles fall in the N-terminal and rRNA-contacting surfaces of the protein, which lie close to the peptidyl transferase centre; p.R32L sits in the 28S rRNA binding region and is predicted to break the Arg32-Asp28 salt bridge. This is the initiating molecular lesion of the disorder.

Genetic context RPL10 hgnc:10298 allele_type: missense variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Hemizygous missense substitutions in males. Loss of function is the predominant demonstrated consequence across the syndromic alleles, shown independently for p.K78E by failed morphant rescue in zebrafish and for p.R116Q by reduced transcript and protein in transfected cells. The p.A64V allele is the documented exception and is modelled separately.

structural constituent of ribosome GO:0003735 ↓ DECREASED

Animal models

rpl10 morpholino knockdown zebrafish Zebrafish measures In vivo complementation with human mRNA carrying p.K78E was used as the functional assay that classified the allele as loss of function.

Downstream

Impaired Late Cytoplasmic 60S Subunit Maturation The altered protein is incorporated into pre-60S particles but cannot complete the final cytoplasmic maturation step.

Show evidence (3 references)

PMID:40861044 SUPPORT Human Clinical

"The RPL10 protein is a 214-amino-acid ribosomal protein that is a critical component of the 60S ribosome subunit."

Establishes the identity and ribosomal role of the affected protein.

PMID:35876338 SUPPORT Human Clinical

"The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt-bridge between Arg32 and Asp28."

Localises a recurrent syndromic allele to the rRNA-binding surface of uL16.

PMID:25316788 SUPPORT Human Clinical

"a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function"

Places the syndromic substitutions near the peptidyl transferase centre and links them to the brain phenotype.

Impaired Late Cytoplasmic 60S Subunit Maturation

uL16 is the sensor for the final cytoplasmic quality-control checkpoint of 60S biogenesis. Correct uL16 placement in the P site is required to dislodge the export adapter Nmd3, which in turn permits Sdo1-stimulated Efl1 to release the anti-association factor Tif6. A missense-altered uL16 traps Nmd3 in the P site, so Nmd3 and Tif6 are not released and the subunit cannot be licensed for translation.

ribosomal large subunit biogenesis GO:0042273 ↓ DECREASED maturation of LSU-rRNA GO:0000470 ↓ DECREASED

Downstream

Reduced Pool of Translation-Competent 60S Subunits Subunits that fail the checkpoint are withheld from the translating pool and targeted for degradation.

Show evidence (4 references)

PMID:28715419 SUPPORT INDIRECT In Vitro

"We previously showed that these T-ALL mutations disrupt late cytoplasmic maturation of the 60S ribosomal subunit, blocking the release of the trans-acting factors Nmd3 and Tif6 in S. cerevisiae."

Defines the conserved biochemical checkpoint that uL16 governs. The allele studied is somatic and leukemia-associated, so this establishes the mechanism of the protein, not of an MRXS35 variant.

PMID:28715419 SUPPORT INDIRECT In Vitro

"define a failure in the removal of Nmd3 as the molecular defect of the T-ALL-associated rpl10-R98S mutation"

Identifies trapped Nmd3 in the P site as the specific molecular lesion of a uL16 missense substitution.

PMID:9443083 SUPPORT INDIRECT In Vitro

"This finding suggests that the QM protein is most likely involved in a late step of the 60S subunit assembly and is added to the 60S ribosomal subunit in the cytoplasm and not in the nucleolus."

Establishes in human cells that this protein joins the 60S subunit late and in the cytoplasm, which is what makes the cytoplasmic checkpoint the relevant step. QM is the original name for the protein now called RPL10; the paper predates the RPL10 nomenclature.

+ 1 more reference

Reduced Pool of Translation-Competent 60S Subunits

Fewer mature 60S subunits reach the cytoplasmic translating pool, lowering the cell's capacity for bulk protein synthesis. In zebrafish, rpl10 suppression reduces bulk translation directly.

ribosome assembly GO:0042255 ↓ DECREASED cytoplasmic translation GO:0002181 ↓ DECREASED

Downstream

Tissue-Specific Translational Vulnerability The same subunit shortfall is felt unevenly across tissues, according to how much RPL10 each normally expresses.

Increased Apoptosis and Impaired Proliferation in the Developing Brain Reduced translational capacity in neural tissue is accompanied by increased apoptosis in the developing brain.

Show evidence (1 reference)

PMID:24706786 SUPPORT INDIRECT In Vitro

"The resulting deficit in ribosomes causes the hypoproliferative phenotype."

Connects the maturation failure to a measurable ribosome deficit and a hypoproliferative cellular consequence, in the yeast uL16 model.

Increased Apoptosis and Impaired Proliferation in the Developing Brain

Neural progenitors and neurons are disproportionately sensitive to reduced ribosome supply, a tissue-specific vulnerability shared across ribosomopathies. rpl10 is expressed preferentially in anterior structures in zebrafish, and its suppression increases brain apoptosis and reduces head size. Nucleolar and ribosome-biogenesis proteins as a class are enriched for human neurodevelopmental phenotypes dominated by microcephaly and cognitive impairment.

neural progenitor cell CL:0011020 neuron CL:0000540

neuron apoptotic process GO:0051402 ↑ INCREASED

Animal models

rpl10 morpholino knockdown zebrafish Zebrafish recapitulates rpl10 suppression reduces bulk translation and increases apoptosis in the developing brain, reproducing the proposed cellular lesion.

Downstream

Impaired Brain Growth and Cerebellar Development

Show evidence (2 references)

PMID:35876338 SUPPORT Model Organism

"RPL10‐associated microcephaly was indeed associated to insufficient proliferation and/or loss of neuroprogenitors cells, along with secondary translational deficits, in RPL10‐depleted zebrafish,"

Names the proliferation half of this node explicitly, which the apoptosis evidence alone does not cover.

PMID:27053602 SUPPORT INDIRECT Model Organism

"dysregulation of ribosomal biogenesis and/or other functions of the nucleolus may disrupt neurodevelopment resulting in such phenotypes as microcephaly and/or cognitive impairment"

Establishes the class-level principle that ribosome-biogenesis failure produces microcephaly and cognitive impairment; RPL10 is named among the nucleolar proteins in this dataset.

Impaired Brain Growth and Cerebellar Development

The cumulative effect on the developing central nervous system is reduced brain growth, presenting as congenital or progressive postnatal microcephaly, with cerebellar hypoplasia (often vermian) on neuroimaging in a subset of patients. This is the tissue-level lesion that produces the cognitive, motor and seizure phenotype.

brain development GO:0007420 ↓ DECREASED

Downstream

Microcephaly

Cerebellar hypoplasia

Global developmental delay

Delayed speech and language development

Absent speech

Ataxia

Secondary microcephaly

Autism Autism is not confined to the milder C-terminal branch; it is named among the defining features of the syndromic disorder itself.

Intellectual disability

Seizure

Show evidence (2 references)

PMID:25316788 SUPPORT Human Clinical

"we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures"

Names the core central nervous system phenotype of the disorder.

PMID:26290468 SUPPORT Human Clinical

"in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"

Documents cerebellar hypoplasia as part of the central nervous system phenotype.

Hypomorphic C-Terminal uL16 Variants Altering Translational Regulation

A distinct, milder branch of the RPL10 allelic series. The C-terminal substitutions p.L206M and p.H213Q, found in autism families, leave basic translation intact while impairing regulation of the translation process, a hypomorphic rather than null behaviour. This is the mechanistic basis for the autism-only end of the RPL10 spectrum and is presented here as a separate node because it does not proceed through the 60S maturation-failure chain above. No modifier is set on the process term deliberately: the cited claim is that regulation of translation is altered while bulk output is preserved, so neither DECREASED nor INCREASED describes it.

translation GO:0006412

Downstream

Autism

Show evidence (1 reference)

PMID:16940977 SUPPORT In Vitro

"We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact."

Establishes the hypomorphic, regulation-specific behaviour of the C-terminal alleles.

p.A64V Increases the Actively Translating Ribosome Population

A second departure from the loss-of-function chain, and in the opposite direction from the C-terminal hypomorphs. The N-terminal p.A64V allele yields a functional protein that complements a conditional lethal yeast rpl10 mutant, yet shifts the polysome profile toward more actively translating ribosomes. It is modelled separately because it can be neither a maturation failure nor a hypomorph, and because the two cousins carrying it are the source of the cerebellar hypoplasia and spondyloepiphyseal dysplasia reported in this disorder. Whether this represents a genuinely opposite route to the same phenotype is unresolved and is recorded as a knowledge gap.

translation GO:0006412 ↑ INCREASED

Downstream

Cerebellar hypoplasia

Spondyloepiphyseal dysplasia

Show evidence (2 references)

PMID:26290468 SUPPORT In Vitro

"unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population"

Records the p.A64V exception, which argues against a uniform loss-of-function model across the allelic series.

PMID:26290468 SUPPORT Human Clinical

"in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"

Ties this allele to the two phenotypes it is the reported source of.

Tissue-Specific Translational Vulnerability

Ribosomes are ubiquitous, yet ribosomopathies produce tissue-restricted phenotypes. RPL10 protein is disproportionately abundant in the tissues this disorder targets outside the brain: it is highly expressed in vertebrate epiphyseal cartilage, and ranks 553rd of 12,000 expressed genes in the human retina. That expression bias is the proposed reason a general shortfall of translation-competent subunits produces retinal degeneration and spondyloepiphyseal dysplasia rather than a uniform systemic defect. The route is inferred from expression data, not demonstrated in patient tissue.

photoreceptor cell CL:0000210

Downstream

Retinal degeneration

Spondyloepiphyseal dysplasia

Show evidence (3 references)

PMID:35876338 SUPPORT INDIRECT Human Clinical

"RPL10 is also expressed in the human retina (Pinelli et al., 2016) at 553rd position out of 12,000 expressed genes."

Gives the retinal expression bias behind the ocular phenotype. This is an expression observation rather than a demonstration of the causal route, hence INDIRECT.

PMID:40861044 SUPPORT INDIRECT Human Clinical

"A high expression of RPL10 protein was observed in the hippocampus of mice (2) and vertebrate epiphyseal cartilage (3)."

Gives the cartilage expression bias behind the skeletal phenotype, on the same inferential footing as the retinal claim.

PMID:35876338 SUPPORT Human Clinical

"Despite ribosomes being ubiquitous, ribosomopathies might result in tissue‐specific impairments, since cell‐ and tissue‐type specific ribosomal proteins expresssion."

States the general principle that a ubiquitous ribosomal defect yields tissue-restricted disease, which is what this node asserts.

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Pathograph

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Phenotypes

26

Cardiovascular 2

Mitral valve prolapse OCCASIONAL HP:0001634

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"Cardiac ultrasound showed mild mitral prolapse and tricuspid prolapse with regurgitation without aortic root dilatation."

Documents echocardiographic mitral valve prolapse in a reported patient.

Abnormal heart morphology OCCASIONAL HP:0001627

Show evidence (1 reference)

PMID:29066376 SUPPORT Human Clinical

"The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."

Associates structural cardiac defects with the recurrent p.K78E allele.

Digestive 1

Feeding difficulties OCCASIONAL HP:0011968

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"He also presented with feeding difficulties, congenital laryngeal stridor, neonatal pneumonia, and neonatal hypoglycemia."

Documents feeding difficulties in the neonatal period.

Ear 1

Hearing impairment OCCASIONAL HP:0000365

Show evidence (1 reference)

PMID:29066376 SUPPORT Human Clinical

"The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."

Associates hearing loss with the recurrent p.K78E allele.

Eye 2

Retinal degeneration OCCASIONAL HP:0000546

Show evidence (2 references)

PMID:35876338 SUPPORT Human Clinical

"In addition to features consistent with RPL10-related disorder, all four boys had retinal degeneration and postnatal microcephaly."

Documents retinal degeneration in all four p.R32L probands.

PMID:35876338 SUPPORT Human Clinical

"at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation"

Records the proposed genotype-phenotype correlation limiting retinal involvement to p.R32L.

Exotropia OCCASIONAL HP:0000577

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies"

Lists exotropia among the features of the complex end of the spectrum.

Genitourinary 3

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"In the first months of life, both newborns presented with congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism."

Documents bilateral cryptorchidism in both reported patients.

Hypospadias OCCASIONAL HP:0000047

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies (cryptorchidism, hypospadias, and vesicoureteral reflux), spondyloepiphyseal dysplasia, and other skeletal anomalies"

Lists hypospadias within the genitourinary anomaly spectrum of the disorder.

Vesicoureteral reflux OCCASIONAL HP:0000076

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"He underwent surgeries for vescicoureteral reflux and bilateral cryptorchidism."

Documents vesicoureteral reflux requiring surgery in a reported patient.

Head and Neck 3

Microcephaly FREQUENT HP:0000252

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"Among 15 individuals with RPL10-related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases."

Gives the reported frequency of microcephaly across the published cohort.

Secondary microcephaly VERY_FREQUENT HP:0005484

Course: PROGRESSIVE

Show evidence (3 references)

PMID:35876338 SUPPORT Human Clinical

"A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies."

Documents progressive postnatal microcephaly as a recurrent feature of the p.R32L cohort.

PMID:35876338 SUPPORT Human Clinical

"Postnatal microcephaly was found as a common feature in our case series (100%) and was highly prevalent in the other patients reported in the literature (75%) with average SDS of OFC of −3."

Gives the frequency behind this band and shows the postnatal form is the common one in this disorder, not the rarer one.

PMID:35876338 SUPPORT Human Clinical

"OFC was normal birth in all 19 patients, but microcephaly was observed in all the patients bearing p.Arg32Leu variant and in 75% of the other group (Table 1)."

Head circumference was normal at birth in all 19 patients, establishing that the microcephaly is acquired rather than congenital.

Abnormal facial shape VERY_FREQUENT HP:0001999

Show evidence (1 reference)

PMID:25846674 SUPPORT Human Clinical

"All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism."

Reports facial dysmorphism as a syndromic feature of the family.

Musculoskeletal 2

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."

Names hypotonia among the hallmark phenotypes.

Spondyloepiphyseal dysplasia OCCASIONAL HP:0002655

Show evidence (1 reference)

PMID:26290468 SUPPORT Human Clinical

"Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders."

Establishes RPL10 as a cause of spondyloepiphyseal dysplasia.

Nervous System 8

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:25846674 SUPPORT Human Clinical

"All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism."

Reports intellectual disability in every affected male of the family (4/4).

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"Patients with MRXS35 mainly present with intellectual disability (ID), psychomotor development delay, speech delay, short stature, craniofacial anomalies, hypotonia, seizures, gastrointestinal problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss."

Lists psychomotor development delay among the core presenting features of MRXS35.

Delayed speech and language development VERY_FREQUENT HP:0000750

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."

Names speech delay as a hallmark phenotype of the disorder.

Absent speech OCCASIONAL HP:0001344

Show evidence (1 reference)

PMID:29066376 SUPPORT Human Clinical

"we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"

Documents absent speech in a severely affected individual.

Seizure FREQUENT HP:0001250

Show evidence (2 references)

PMID:35876338 SUPPORT Human Clinical

"Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies."

Names epilepsy among the defining features of the syndrome.

PMID:29066376 SUPPORT Human Clinical

"The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."

Associates seizures with the recurrent p.K78E allele alongside the other severe features.

Autism FREQUENT HP:0000717

Show evidence (1 reference)

PMID:16940977 SUPPORT Human Clinical

"We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism."

The original report linking RPL10 to autism in two independent families.

Cerebellar hypoplasia OCCASIONAL HP:0001321

Show evidence (1 reference)

PMID:26290468 SUPPORT Human Clinical

"Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"

Reports cerebellar hypoplasia in both affected cousins carrying p.A64V.

Ataxia OCCASIONAL HP:0001251

Show evidence (1 reference)

PMID:29066376 SUPPORT Human Clinical

"we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"

Documents ataxia in an affected male.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:25846674 SUPPORT Human Clinical

"with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism"

Reports amniotic fluid excess in 3 of 4 affected pregnancies.

Respiratory 1

Laryngomalacia OCCASIONAL HP:0001601

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies"

Lists laryngomalacia among the features of the complex end of the spectrum.

Growth 2

Growth delay FREQUENT HP:0001510

Show evidence (1 reference)

PMID:25316788 SUPPORT Human Clinical

"Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures."

Names growth retardation as one of three hallmark features of the index pedigree.

Short stature FREQUENT HP:0004322

Show evidence (2 references)

PMID:40861044 SUPPORT Human Clinical

"At his last clinical evaluation at 9 years of age, case II presented with ID, speech delay, short stature, and craniofacial anomalies."

Documents short stature in a genetically confirmed patient.

PMID:35876338 SUPPORT Human Clinical

"Short stature was absent in p.Arg32Leu patients while it was detected in 62% (5/8) of the literature group."

Gives the count behind this frequency band, and records that short stature is allele-dependent — absent in the p.R32L group, 62% in the rest.

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Genetic Associations

1

RPL10 (Causative)

Gene: RPL10 hgnc:10298 variant_origin: GERMLINE

Show evidence (4 references)

PMID:25316788 SUPPORT Human Clinical

"we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD)"

Establishes RPL10 as the causative gene for the syndromic X-linked phenotype.

PMID:40861044 SUPPORT Human Clinical

"The X-linked syndromic intellectual developmental disorder-35 (MRXS35; OMIM#300998) is caused by variants in the RPL10 gene (OMIM*312173) on chromosome Xq28."

Names the disorder, its OMIM identifier, and the causative gene and locus.

PMID:25316788 SUPPORT Model Organism

"using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant"

Direct functional demonstration of loss of function for the recurrent p.K78E allele.

+ 1 more reference

💊

Medical Actions

7

Multidisciplinary Supportive and Developmental Care

Action: Supportive care Ontology label: Supportive Care NCIT:C15747

There is no disease-modifying therapy, no approved drug, no gene therapy and no interventional clinical trial for MRXS35. Management is entirely symptomatic and supportive: early developmental intervention plus coordinated surveillance of growth, seizures, vision (including retinal assessment), hearing, cardiac structure, genitourinary anatomy and airway. Of the recently reported neonatal presentations, the hypoglycemia and the pneumonia are documented as transient and improving with routine management; no such course is reported for the laryngeal stridor or the feeding difficulty.

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"The symptoms of neonatal hypoglycemia and hypoglycemia (caused by bacteria) were transient, and both cases showed significant improvement with appropriate interventions."

Documents that the neonatal complications respond to supportive management.

Speech and Language Therapy

Action: Speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech delay is a hallmark feature and expressive language is disproportionately affected, with some individuals non-verbal into school age, so early speech therapy with augmentative and alternative communication where needed is a core intervention.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"At the last clinical evaluation at the age of 9 years, he was still non-verbal."

Documents the persistent expressive language impairment this intervention targets.

Physical Therapy and Motor Rehabilitation

Action: Physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Hypotonia, delayed independent walking and tiptoe gait are recurrent, and cerebellar involvement contributes to ataxia in a subset, so physiotherapy targeting tone, gait and mobility is standard.

Target Phenotypes: Hypotonia HP:0001252

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"In the first months of life, he showed generalized hypotonia with severe orofacial hypotonia but normal deep tendon reflexes."

Documents the generalized hypotonia this intervention targets.

Occupational Therapy

Action: Occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Hypotonia, brachydactyly and clinodactyly, and the global developmental delay affect fine motor skill and daily function, so occupational therapy sits alongside physiotherapy and speech therapy in the standard developmental package. No RPL10-specific protocol exists.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:40861044 SUPPORT Human Clinical

"In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."

Names the developmental delay and hypotonia this intervention targets.

Antiseizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Seizures are a core feature and may be refractory and early-onset, requiring antiseizure medication. No RPL10-specific antiseizure regimen has been established and no agent has been shown to be preferentially effective in this disorder, so treatment follows standard epilepsy practice for the observed seizure semiology.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:29066376 SUPPORT Human Clinical

"we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"

Documents the refractory early-onset epilepsy that motivates antiseizure pharmacotherapy.

Surgical Correction of Congenital Anomalies

Action: Surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cryptorchidism (usually bilateral) and vesicoureteral reflux are the anomalies most often requiring operative management; adenoidectomy has been performed for obstructive sleep disorder.

Target Phenotypes: Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:35876338 SUPPORT Human Clinical

"He underwent surgeries for vescicoureteral reflux and bilateral cryptorchidism."

Documents the surgical management of the two commonest genitourinary anomalies.

Genetic Counseling and Carrier Testing

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Transmission is usually from an unaffected heterozygous mother, so carrier testing of the mother and at-risk female relatives, with counselling on 50% transmission risk to sons, is central to management. Documented skewed X inactivation in carriers supports their unaffected status but does not guarantee it across the allelic series.

Show evidence (1 reference)

PMID:25316788 SUPPORT Human Clinical

"the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation"

Establishes the maternal carrier transmission pattern that counselling addresses.

🔬

Diagnosis

1

Trio Exome or Genome Sequencing

There are no formal clinical diagnostic criteria and the phenotype is not specific enough to be separated clinically from other X-linked intellectual disability, so molecular diagnosis is definitive. Every reported case was ascertained by exome sequencing, in most instances after a normal array-CGH and negative targeted testing (including fragile X). The trio design matters both for detecting the occasional de novo variant and for confirming maternal carrier status, which drives recurrence counselling. Most RPL10 missense alleles are initially returned as variants of uncertain significance, so functional follow-up may be required for reclassification. The clinical differential is other syndromic X-linked intellectual disability of similar presentation, in particular MECP2, KDM5C, USP9X and MSL3. None is separable from MRXS35 on phenotype alone, which is why the diagnosis is molecular; a multi-gene panel or exome covers them together. Chromosomal microarray is not merely historical here. RPL10 sits inside the recurrent Xq28 duplication interval alongside FLNA and GDI1, and multigenic Xq28 copy-number gains produce their own intellectual disability syndromes that are distinct from MRXS35 and not attributable to RPL10. Microarray is what separates them from a point mutation in this gene.

Show evidence (2 references)

PMID:40861044 SUPPORT Human Clinical

"Due to their multiple congenital anomalies, whole-exome sequencing (WES) was recommended and conducted."

Establishes exome sequencing as the diagnostic route in practice.

PMID:40861044 SUPPORT Human Clinical

"The Sanger sequencing also confirmed that the same hemizygous variant was derived from their respective heterozygous carrier mothers, and their respective fathers were normal."

Shows the role of parental testing in confirming maternal carrier status.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

No population-based prevalence or incidence estimate exists. The literature quantifies the disorder only as a cumulative case count. Cappuccio et al. reviewed publications from 2006 to 2022 and retrieved 15 individuals with pathogenic RPL10 variants; Xu et al. counted 19 previously reported male patients carrying seven missense variants over 2014-2024. The two figures are the same cohort counted at different points, not a disagreement: Cappuccio's 15 is the pre-existing literature, and their own total including the four new p.R32L probands is 19, which is the number Xu then carried forward. Reported patients come from Europe, North America and East Asia with no founder effect; the apparent geography reflects exome-sequencing access.

Show evidence (3 references)

PMID:35876338 SUPPORT Human Clinical

"Hemizygous pathogenic variants in RPL10 have been described in only 15 patients with a wide spectrum of manifestations"

Gives the pre-existing literature count that Cappuccio started from.

PMID:35876338 SUPPORT Human Clinical

"A total of 19 males with RPL10‐related disorder, including the four individuals in the present study, are known so far."

Gives the same paper's total including its four new probands, which is the 19 the later count carries forward.

PMID:40861044 SUPPORT Human Clinical

"In the past decade (2014∼2024), only seven missense RPL10 gene variants have been identified in the 19 previously reported male patients."

Gives the updated cumulative case and allele count as of 2025.

🐁

Animal Models

1

rpl10 morpholino knockdown zebrafish

Morpholino suppression of endogenous rpl10 in developing zebrafish embryos. The model was used both to establish that rpl10 loss produces a microcephaly-like phenotype and, by in vivo complementation, to test whether the human p.K78E allele retains function.

Species

Zebrafish

Genotype

rpl10 translation-blocking morpholino knockdown, with p.K78E mRNA complementation

Publication

PMID:25316788

Pathograph links

Increased Apoptosis and Impaired Proliferation in the Developing Brain recapitulates fidelity: moderate observes: tissue rpl10 suppression reduces bulk translation and increases apoptosis in the developing brain, reproducing the proposed cellular lesion.

Limitations: Transient morpholino knockdown models complete loss of rpl10, whereas the human disorder is caused by hemizygous missense alleles that retain a protein product; morphant phenotypes are also susceptible to off-target effects not controlled by a genetic mutant in this study.

Readouts

Brain apoptosis in morphant embryos

Direction: INCREASED

Interpretation: Cellular correlate of the apoptosis node in this model.

Show evidence (1 reference)

PMID:25316788 SUPPORT Model Organism

"suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain"

Reports the apoptosis measurement behind this readout.

Show evidence (1 reference)

PMID:25316788 SUPPORT Model Organism

"To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish."

Establishes the model as the system used to test this mechanism.

RPL10 Missense Substitution in uL16 measures fidelity: moderate observes: tissue In vivo complementation with human mRNA carrying p.K78E was used as the functional assay that classified the allele as loss of function.

Limitations: The assay reports on rescue of a morphant phenotype in a fish embryo and does not measure the biochemical step (60S maturation) that the substitution is inferred to disrupt.

Show evidence (1 reference)

PMID:25316788 SUPPORT Model Organism

"Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant."

States the complementation result that this model contributes.

Show evidence (1 reference)

PMID:25316788 SUPPORT Model Organism

"We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos"

Establishes that this model is informative for the disorder: endogenous rpl10 is enriched in the anterior structures that the human phenotype affects, and its suppression reproduces the head-size deficit.

{ }

Source YAML

click to show

name: Intellectual Disability X-linked Syndromic 35
creation_date: '2026-09-07T00:00:00Z'
category: Genetic
parents:
- Neurodevelopmental Disorder
- X-linked Disorder
- Ribosomopathy
disease_term:
  preferred_term: intellectual disability, X-linked, syndromic, 35
  term:
    id: MONDO:0030908
    label: intellectual disability, X-linked, syndromic, 35
synonyms:
- MRXS35
- syndromic X-linked intellectual disability 35
- intellectual developmental disorder, X-linked, syndromic, 35
- mental retardation, X-linked, syndromic, 35
- RPL10-related disorder
- RPL10-related syndromic X-linked intellectual disability
description: >
  Syndromic X-linked intellectual disability 35 (MRXS35; OMIM 300998) is an
  ultra-rare X-linked ribosomopathy caused by hemizygous missense variants in
  RPL10 at Xq28. RPL10 encodes uL16, a 214-amino-acid protein of the large (60S)
  ribosomal subunit that sits close to the peptidyl transferase centre and is
  required for the final cytoplasmic maturation step at which the export adapter
  Nmd3 and the anti-association factor Tif6 are released, licensing the subunit
  to enter translation.

  Affected males present with intellectual disability and psychomotor delay,
  speech delay that is frequently absent speech, microcephaly (congenital or
  progressive postnatal), growth retardation and short stature, hypotonia,
  seizures that may be refractory and early-onset, craniofacial dysmorphism, and
  a variable set of congenital anomalies spanning genitourinary (cryptorchidism,
  hypospadias, vesicoureteral reflux), cardiac, ophthalmological (exotropia,
  retinal degeneration), skeletal (spondyloepiphyseal dysplasia), and airway
  (laryngomalacia) systems. Cerebellar hypoplasia is seen on neuroimaging in a
  subset. Transmission is usually from an unaffected carrier mother, with skewed
  X inactivation documented in carriers; de novo occurrence has been reported.

  IMPORTANT SCOPE NOTE — the RPL10 allelic series is broad and this entry covers
  the syndromic end of it. The C-terminal substitutions p.L206M and p.H213Q were
  originally reported as autism susceptibility alleles (AUTSX5, OMIM 300847) and
  behave as hypomorphs that preserve basic translation; they are modelled here as
  a distinct milder branch of the same gene's mechanism, not as MRXS35 proper.
  Separately, somatic RPL10 variants (notably p.R98S) are recurrent drivers in
  T-cell acute lymphoblastic leukemia. That is an entirely distinct somatic
  disease context and must not be conflated with this germline
  neurodevelopmental disorder; R98S yeast work is cited here only to establish
  the conserved biochemical role of uL16 in 60S maturation, and every such item
  is graded accordingly.
references:
- reference: PMID:25316788
  title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment
    and causes X-linked microcephaly in humans.
  findings: []
- reference: PMID:35876338
  title: Postnatal microcephaly and retinal involvement expand the phenotype of RPL10-related
    disorder.
  findings: []
- reference: PMID:40861044
  title: 'Case Report: Identification of a novel hemizygous missense RPL10 gene variant
    in two unrelated patients.'
  findings: []
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    Affected individuals are hemizygous males. In the pedigrees through which the
    disorder was defined the variant was maternally transmitted by an unaffected
    carrier, and skewed X inactivation was documented in carrier females,
    consistent with causality. Expressivity in males is markedly variable, from
    intellectual disability with dysmorphism to a severe multisystem phenotype
    with refractory epilepsy. De novo occurrence has been reported once.
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation"
    explanation: States the X-linked recessive segregation and the skewed X inactivation
      in carrier females.
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first instance that a de novo mutation in RPL10 has been reported."
    explanation: Documents that de novo occurrence, while the exception, does happen.
genetic:
- name: RPL10
  association: Causative
  variant_origin: GERMLINE
  gene_term:
    preferred_term: RPL10
    term:
      id: hgnc:10298
      label: RPL10
  notes: >
    RPL10 (Xq28; reference transcript NM_006013.5, seven exons) encodes uL16, a
    214-amino-acid structural component of the 60S ribosomal subunit. Every
    reported MRXS35 allele is missense; no truncating allele has been described,
    consistent with complete loss of this core ribosomal protein being
    incompatible with viability. Reported syndromic substitutions cluster in the
    N-terminal and rRNA-contacting regions (p.R32L, p.A64V, p.K78E, p.R116Q),
    whereas the C-terminal p.L206M and p.H213Q alleles were reported in autism
    families and behave as hypomorphs. Functional data support loss of function:
    p.K78E fails to rescue rpl10 morphant zebrafish, and p.R116Q reduces RPL10
    mRNA and protein in transfected cells. The p.A64V allele is the informative
    exception, producing a functional protein that instead increases the
    actively translating ribosome pool, so "loss of function" should not be
    assumed uniformly across the allelic series.

    RPL10 is strongly constrained in population reference data (gnomAD v2
    pLI 0.997, missense Z 4.08), which fits the missense-only allelic spectrum:
    partial-loss-of-function substitutions are compatible with viability where a
    null allele is not. These constraint statistics are database values rather
    than a finding quoted from a paper, so they are recorded here rather than as
    an evidence item. The gnomAD absence of a specific pathogenic allele is cited
    separately, on the RPL10 Missense Substitution in uL16 pathophysiology node.
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD)"
    explanation: Establishes RPL10 as the causative gene for the syndromic X-linked
      phenotype.
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The X-linked syndromic intellectual developmental disorder-35 (MRXS35; OMIM#300998) is caused by variants in the RPL10 gene (OMIM*312173) on chromosome Xq28."
    explanation: Names the disorder, its OMIM identifier, and the causative gene and
      locus.
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant"
    explanation: Direct functional demonstration of loss of function for the recurrent
      p.K78E allele.
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our in vitro functional analysis indicated a loss-of-function effect of RPL10 gene variants."
    explanation: Independent in vitro replication of the loss-of-function mechanism
      for a second allele.
pathophysiology:
- name: RPL10 Missense Substitution in uL16
  genetic_context:
    gene:
      preferred_term: RPL10
      term:
        id: hgnc:10298
        label: RPL10
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >
      Hemizygous missense substitutions in males. Loss of function is the
      predominant demonstrated consequence across the syndromic alleles, shown
      independently for p.K78E by failed morphant rescue in zebrafish and for
      p.R116Q by reduced transcript and protein in transfected cells. The p.A64V
      allele is the documented exception and is modelled separately.
  description: >
    A hemizygous missense substitution alters uL16, the 60S ribosomal subunit
    protein encoded by RPL10. The syndromic alleles fall in the N-terminal and
    rRNA-contacting surfaces of the protein, which lie close to the peptidyl
    transferase centre; p.R32L sits in the 28S rRNA binding region and is
    predicted to break the Arg32-Asp28 salt bridge. This is the initiating
    molecular lesion of the disorder.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: structural constituent of ribosome
    modifier: DECREASED
    term:
      id: GO:0003735
      label: structural constituent of ribosome
  downstream:
  - target: Impaired Late Cytoplasmic 60S Subunit Maturation
    causal_link_type: DIRECT
    description: >
      The altered protein is incorporated into pre-60S particles but cannot
      complete the final cytoplasmic maturation step.
    evidence:
    - reference: PMID:24706786
      reference_title: Bypass of the pre-60S ribosomal quality control as a pathway
        to oncogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "This mutation causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation."
      explanation: >-
        Establishes in yeast that an rpl10/uL16 missense substitution acts by
        failing late 60S maturation. Cited for the conserved biochemistry of
        uL16; the allele studied is the somatic leukemia variant, not an MRXS35
        allele, hence INDIRECT.
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The RPL10 protein is a 214-amino-acid ribosomal protein that is a critical component of the 60S ribosome subunit."
    explanation: Establishes the identity and ribosomal role of the affected protein.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt-bridge between Arg32 and Asp28."
    explanation: Localises a recurrent syndromic allele to the rRNA-binding surface
      of uL16.
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function"
    explanation: Places the syndromic substitutions near the peptidyl transferase centre
      and links them to the brain phenotype.
- name: Impaired Late Cytoplasmic 60S Subunit Maturation
  description: >
    uL16 is the sensor for the final cytoplasmic quality-control checkpoint of
    60S biogenesis. Correct uL16 placement in the P site is required to dislodge
    the export adapter Nmd3, which in turn permits Sdo1-stimulated Efl1 to
    release the anti-association factor Tif6. A missense-altered uL16 traps Nmd3
    in the P site, so Nmd3 and Tif6 are not released and the subunit cannot be
    licensed for translation.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: ribosomal large subunit biogenesis
    modifier: DECREASED
    term:
      id: GO:0042273
      label: ribosomal large subunit biogenesis
  - preferred_term: maturation of LSU-rRNA
    modifier: DECREASED
    term:
      id: GO:0000470
      label: maturation of LSU-rRNA
  downstream:
  - target: Reduced Pool of Translation-Competent 60S Subunits
    causal_link_type: DIRECT
    description: >
      Subunits that fail the checkpoint are withheld from the translating pool
      and targeted for degradation.
    evidence:
    - reference: PMID:28715419
      reference_title: The T-cell leukemia related rpl10-R98S mutant traps the 60S
        export adapter Nmd3 in the ribosomal P site in yeast.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Consequently, these mutant ribosomes do not efficiently pass the cytoplasmic quality control checkpoint and are blocked from engaging in translation."
      explanation: >-
        States the causal step from failed maturation to exclusion from the
        translating pool. Yeast biochemistry on the leukemia allele, cited for
        the conserved uL16 checkpoint rather than for an MRXS35 allele, hence
        INDIRECT.
  evidence:
  - reference: PMID:28715419
    reference_title: The T-cell leukemia related rpl10-R98S mutant traps the 60S export
      adapter Nmd3 in the ribosomal P site in yeast.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "We previously showed that these T-ALL mutations disrupt late cytoplasmic maturation of the 60S ribosomal subunit, blocking the release of the trans-acting factors Nmd3 and Tif6 in S. cerevisiae."
    explanation: >-
      Defines the conserved biochemical checkpoint that uL16 governs. The allele
      studied is somatic and leukemia-associated, so this establishes the
      mechanism of the protein, not of an MRXS35 variant.
  - reference: PMID:28715419
    reference_title: The T-cell leukemia related rpl10-R98S mutant traps the 60S export
      adapter Nmd3 in the ribosomal P site in yeast.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "define a failure in the removal of Nmd3 as the molecular defect of the T-ALL-associated rpl10-R98S mutation"
    explanation: >-
      Identifies trapped Nmd3 in the P site as the specific molecular lesion of a
      uL16 missense substitution.
  - reference: PMID:9443083
    reference_title: Assembly of the QM protein onto the 60S ribosomal subunit occurs
      in the cytoplasm.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "This finding suggests that the QM protein is most likely involved in a late step of the 60S subunit assembly and is added to the 60S ribosomal subunit in the cytoplasm and not in the nucleolus."
    explanation: >-
      Establishes in human cells that this protein joins the 60S subunit late and
      in the cytoplasm, which is what makes the cytoplasmic checkpoint the
      relevant step. QM is the original name for the protein now called RPL10;
      the paper predates the RPL10 nomenclature.
  - reference: PMID:9443083
    reference_title: Assembly of the QM protein onto the 60S ribosomal subunit occurs
      in the cytoplasm.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "the gene for this protein has also been shown in Saccharomyces cerevisiae to encode an essential 60S ribosomal subunit protein that is required for the joining of the 40S and 60S subunits"
    explanation: >-
      States the subunit-joining requirement that failed maturation removes. Cited
      under the QM name for RPL10.
- name: Reduced Pool of Translation-Competent 60S Subunits
  description: >
    Fewer mature 60S subunits reach the cytoplasmic translating pool, lowering
    the cell's capacity for bulk protein synthesis. In zebrafish, rpl10
    suppression reduces bulk translation directly.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: ribosome assembly
    modifier: DECREASED
    term:
      id: GO:0042255
      label: ribosome assembly
  - preferred_term: cytoplasmic translation
    modifier: DECREASED
    term:
      id: GO:0002181
      label: cytoplasmic translation
  downstream:
  - target: Tissue-Specific Translational Vulnerability
    causal_link_type: DIRECT
    description: >
      The same subunit shortfall is felt unevenly across tissues, according to how
      much RPL10 each normally expresses.
  - target: Increased Apoptosis and Impaired Proliferation in the Developing Brain
    causal_link_type: DIRECT
    description: >
      Reduced translational capacity in neural tissue is accompanied by increased
      apoptosis in the developing brain.
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain"
      explanation: Links reduced bulk translation to brain apoptosis in the same experiment.
  evidence:
  - reference: PMID:24706786
    reference_title: Bypass of the pre-60S ribosomal quality control as a pathway to
      oncogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "The resulting deficit in ribosomes causes the hypoproliferative phenotype."
    explanation: >-
      Connects the maturation failure to a measurable ribosome deficit and a
      hypoproliferative cellular consequence, in the yeast uL16 model.
- name: Increased Apoptosis and Impaired Proliferation in the Developing Brain
  description: >
    Neural progenitors and neurons are disproportionately sensitive to reduced
    ribosome supply, a tissue-specific vulnerability shared across
    ribosomopathies. rpl10 is expressed preferentially in anterior structures in
    zebrafish, and its suppression increases brain apoptosis and reduces head
    size. Nucleolar and ribosome-biogenesis proteins as a class are enriched for
    human neurodevelopmental phenotypes dominated by microcephaly and cognitive
    impairment.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0051402
      label: neuron apoptotic process
  downstream:
  - target: Impaired Brain Growth and Cerebellar Development
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos"
      explanation: Ties loss of rpl10 function directly to reduced head size in a developing
        vertebrate.
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RPL10‐associated microcephaly was indeed associated to insufficient proliferation and/or loss of neuroprogenitors cells, along with secondary translational deficits, in RPL10‐depleted zebrafish,"
    explanation: Names the proliferation half of this node explicitly, which the
      apoptosis evidence alone does not cover.
  - reference: PMID:27053602
    reference_title: Nucleolar Enrichment of Brain Proteins with Critical Roles in
      Human Neurodevelopment.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "dysregulation of ribosomal biogenesis and/or other functions of the nucleolus may disrupt neurodevelopment resulting in such phenotypes as microcephaly and/or cognitive impairment"
    explanation: >-
      Establishes the class-level principle that ribosome-biogenesis failure
      produces microcephaly and cognitive impairment; RPL10 is named among the
      nucleolar proteins in this dataset.
- name: Impaired Brain Growth and Cerebellar Development
  description: >
    The cumulative effect on the developing central nervous system is reduced
    brain growth, presenting as congenital or progressive postnatal microcephaly,
    with cerebellar hypoplasia (often vermian) on neuroimaging in a subset of
    patients. This is the tissue-level lesion that produces the cognitive,
    motor and seizure phenotype.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: brain development
    modifier: DECREASED
    term:
      id: GO:0007420
      label: brain development
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27053602
      reference_title: Nucleolar Enrichment of Brain Proteins with Critical Roles in
        Human Neurodevelopment.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Microcephaly and/or cognitive impairment were the most common phenotypic manifestations."
      explanation: >-
        Supports the step from a ribosome-biogenesis brain lesion to microcephaly
        as the expected phenotypic output. The claim is made at the level of the
        nucleolar protein class (which includes RPL10) rather than of this
        disorder, hence INDIRECT. Graded OTHER because this sentence reports an
        association with human neurodevelopmental phenotypes drawn from the
        literature, not a result of the paper's own rat experiments.
    - reference: PMID:35876338
      reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
        of RPL10-related disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Postnatal microcephaly was found as a common feature in our case series (100%) and was highly prevalent in the other patients reported in the literature (75%) with average SDS of OFC of −3."
      explanation: Direct on-disease evidence that the brain-growth lesion presents as
        microcephaly, with its frequency.
  - target: Cerebellar hypoplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26290468
      reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
        Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"
      explanation: Documents cerebellar hypoplasia as an output of the brain-development
        lesion in affected males.
  - target: Global developmental delay
    causal_link_type: DIRECT
  - target: Delayed speech and language development
    causal_link_type: DIRECT
  - target: Absent speech
    causal_link_type: DIRECT
  - target: Ataxia
    causal_link_type: DIRECT
  - target: Secondary microcephaly
    causal_link_type: DIRECT
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Autism is not confined to the milder C-terminal branch; it is named among
      the defining features of the syndromic disorder itself.
    evidence:
    - reference: PMID:35876338
      reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
        of RPL10-related disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies."
      explanation: Places autism spectrum disorder within the syndromic phenotype, not
        only the autism-only allelic branch.
  - target: Intellectual disability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function."
      explanation: >-
        States that the RPL10 lesion impairs brain function as well as brain
        formation, which is the step from the tissue lesion to the cognitive
        phenotype.
  - target: Seizure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures."
      explanation: Places seizures alongside microcephaly as an output of the same
        RPL10-driven brain lesion in one pedigree.
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures"
    explanation: Names the core central nervous system phenotype of the disorder.
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"
    explanation: Documents cerebellar hypoplasia as part of the central nervous system
      phenotype.
- name: Hypomorphic C-Terminal uL16 Variants Altering Translational Regulation
  description: >
    A distinct, milder branch of the RPL10 allelic series. The C-terminal
    substitutions p.L206M and p.H213Q, found in autism families, leave basic
    translation intact while impairing regulation of the translation process,
    a hypomorphic rather than null behaviour. This is the mechanistic basis for
    the autism-only end of the RPL10 spectrum and is presented here as a separate
    node because it does not proceed through the 60S maturation-failure chain
    above. No modifier is set on the process term deliberately: the cited claim is
    that regulation of translation is altered while bulk output is preserved, so
    neither DECREASED nor INCREASED describes it.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:16940977
    reference_title: Mutations in the ribosomal protein gene RPL10 suggest a novel
      modulating disease mechanism for autism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact."
    explanation: Establishes the hypomorphic, regulation-specific behaviour of the
      C-terminal alleles.
- name: p.A64V Increases the Actively Translating Ribosome Population
  description: >
    A second departure from the loss-of-function chain, and in the opposite
    direction from the C-terminal hypomorphs. The N-terminal p.A64V allele yields
    a functional protein that complements a conditional lethal yeast rpl10 mutant,
    yet shifts the polysome profile toward more actively translating ribosomes.
    It is modelled separately because it can be neither a maturation failure nor a
    hypomorph, and because the two cousins carrying it are the source of the
    cerebellar hypoplasia and spondyloepiphyseal dysplasia reported in this
    disorder. Whether this represents a genuinely opposite route to the same
    phenotype is unresolved and is recorded as a knowledge gap.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: translation
    modifier: INCREASED
    term:
      id: GO:0006412
      label: translation
  downstream:
  - target: Cerebellar hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spondyloepiphyseal dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population"
    explanation: Records the p.A64V exception, which argues against a uniform loss-of-function
      model across the allelic series.
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"
    explanation: Ties this allele to the two phenotypes it is the reported source of.
- name: Tissue-Specific Translational Vulnerability
  description: >
    Ribosomes are ubiquitous, yet ribosomopathies produce tissue-restricted
    phenotypes. RPL10 protein is disproportionately abundant in the tissues this
    disorder targets outside the brain: it is highly expressed in vertebrate
    epiphyseal cartilage, and ranks 553rd of 12,000 expressed genes in the human
    retina. That expression bias is the proposed reason a general shortfall of
    translation-competent subunits produces retinal degeneration and
    spondyloepiphyseal dysplasia rather than a uniform systemic defect. The route
    is inferred from expression data, not demonstrated in patient tissue.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  downstream:
  - target: Retinal degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spondyloepiphyseal dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "RPL10 is also expressed in the human retina (Pinelli et al., 2016) at 553rd position out of 12,000 expressed genes."
    explanation: >-
      Gives the retinal expression bias behind the ocular phenotype. This is an
      expression observation rather than a demonstration of the causal route,
      hence INDIRECT.
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A high expression of RPL10 protein was observed in the hippocampus of mice (2) and vertebrate epiphyseal cartilage (3)."
    explanation: >-
      Gives the cartilage expression bias behind the skeletal phenotype, on the
      same inferential footing as the retinal claim.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite ribosomes being ubiquitous, ribosomopathies might result in tissue‐specific impairments, since cell‐ and tissue‐type specific ribosomal proteins expresssion."
    explanation: States the general principle that a ubiquitous ribosomal defect yields
      tissue-restricted disease, which is what this node asserts.
phenotypes:
- name: Intellectual disability
  category: Neurological
  description: >
    Present in essentially all reported affected males, ranging from mild to
    severe. In the Thevenon family all four affected males had apparent
    intellectual disability with psychomotor delay.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:25846674
    reference_title: RPL10 mutation segregating in a family with X-linked syndromic
      Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism."
    explanation: Reports intellectual disability in every affected male of the family
      (4/4).
- name: Global developmental delay
  category: Neurological
  description: >
    Psychomotor development delay is a defining feature, with delayed independent
    walking commonly reported between 2 and 4 years.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with MRXS35 mainly present with intellectual disability (ID), psychomotor development delay, speech delay, short stature, craniofacial anomalies, hypotonia, seizures, gastrointestinal problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss."
    explanation: Lists psychomotor development delay among the core presenting features
      of MRXS35.
- name: Delayed speech and language development
  category: Neurological
  description: >
    Speech delay is near-universal and disproportionate to overall development;
    several reported individuals remained non-verbal into school age.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."
    explanation: Names speech delay as a hallmark phenotype of the disorder.
- name: Absent speech
  category: Neurological
  description: >
    At the severe end of the spectrum speech may be entirely absent, as in the
    18-year-old male with the de novo p.K78E allele.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"
    explanation: Documents absent speech in a severely affected individual.
- name: Microcephaly
  category: Neurological
  description: >
    Microcephaly is a hallmark of the syndromic phenotype and was reported in
    roughly half of the first 15 published individuals. It is almost always
    postnatal in onset rather than congenital; see the Secondary microcephaly
    entry, which carries the higher frequency and the head-circumference data.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 15 individuals with RPL10-related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases."
    explanation: Gives the reported frequency of microcephaly across the published
      cohort.
- name: Secondary microcephaly
  category: Neurological
  description: >
    Progressive postnatal microcephaly, with head circumference falling to around
    -2 to -3 SD during childhood. Head circumference is normal at birth in all
    reported patients, so the microcephaly of this disorder is predominantly
    secondary: 100% of the p.R32L series and 75% of the previously published
    patients. It is proposed as a clinical clue to the disorder.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Secondary microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies."
    explanation: Documents progressive postnatal microcephaly as a recurrent feature
      of the p.R32L cohort.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatal microcephaly was found as a common feature in our case series (100%) and was highly prevalent in the other patients reported in the literature (75%) with average SDS of OFC of −3."
    explanation: Gives the frequency behind this band and shows the postnatal form is
      the common one in this disorder, not the rarer one.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OFC was normal birth in all 19 patients, but microcephaly was observed in all the patients bearing p.Arg32Leu variant and in 75% of the other group (Table 1)."
    explanation: Head circumference was normal at birth in all 19 patients, establishing
      that the microcephaly is acquired rather than congenital.
- name: Seizure
  category: Neurological
  description: >
    Seizures are a core feature and can be refractory and early in onset. Epilepsy
    is listed among the defining manifestations of the RPL10-related syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies."
    explanation: Names epilepsy among the defining features of the syndrome.
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."
    explanation: Associates seizures with the recurrent p.K78E allele alongside the
      other severe features.
- name: Autism
  category: Behavioral
  description: >
    Autism spectrum disorder is part of the RPL10 phenotypic spectrum and was the
    presentation through which the gene was first implicated, via the C-terminal
    p.L206M and p.H213Q alleles. Poor eye contact, stereotypies and
    self-injurious behaviour are described in syndromic cases as well.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:16940977
    reference_title: Mutations in the ribosomal protein gene RPL10 suggest a novel
      modulating disease mechanism for autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism."
    explanation: The original report linking RPL10 to autism in two independent families.
- name: Cerebellar hypoplasia
  category: Neurological
  description: >
    Cerebellar hypoplasia, frequently affecting the vermis, is seen on brain MRI
    in a subset of patients, and a clinical cerebellar syndrome was present in
    2 of 4 affected males in the Thevenon family.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED)"
    explanation: Reports cerebellar hypoplasia in both affected cousins carrying p.A64V.
- name: Ataxia
  category: Neurological
  description: >
    Ataxia is reported in severely affected individuals and is consistent with the
    cerebellar involvement seen on neuroimaging.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"
    explanation: Documents ataxia in an affected male.
- name: Hypotonia
  category: Neurological
  description: >
    Hypotonia, sometimes generalized with severe orofacial involvement, is a
    recognized feature and contributes to early feeding difficulty.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."
    explanation: Names hypotonia among the hallmark phenotypes.
- name: Growth delay
  category: Growth
  description: >
    Growth retardation is a hallmark of the syndromic phenotype and was one of the
    three cardinal features of the index pedigree.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures."
    explanation: Names growth retardation as one of three hallmark features of the
      index pedigree.
- name: Short stature
  category: Growth
  description: >
    Short stature is among the principal presenting features, but it is
    allele-dependent: 62% (5/8) of the previously published patients, and absent
    from the p.R32L group entirely, some of whom are of normal or above-average
    stature. The band reflects the literature group.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At his last clinical evaluation at 9 years of age, case II presented with ID, speech delay, short stature, and craniofacial anomalies."
    explanation: Documents short stature in a genetically confirmed patient.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature was absent in p.Arg32Leu patients while it was detected in 62% (5/8) of the literature group."
    explanation: >-
      Gives the count behind this frequency band, and records that short stature
      is allele-dependent — absent in the p.R32L group, 62% in the rest.
- name: Abnormal facial shape
  category: Craniofacial
  description: >
    Craniofacial dysmorphism is consistently present but not pathognomonic.
    Reported features include long face, narrow and down-slanting palpebral
    fissures, ptosis, epicanthus, depressed nasal root, long flat philtrum, thin
    upper lip, high-arched palate, microretrognathia and protruding ears.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:25846674
    reference_title: RPL10 mutation segregating in a family with X-linked syndromic
      Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism."
    explanation: Reports facial dysmorphism as a syndromic feature of the family.
- name: Cryptorchidism
  category: Genitourinary
  description: >
    Cryptorchidism, often bilateral and surgically corrected, is one of the most
    consistently reported congenital anomalies.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the first months of life, both newborns presented with congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism."
    explanation: Documents bilateral cryptorchidism in both reported patients.
- name: Hypospadias
  category: Genitourinary
  description: >
    Hypospadias is part of the genitourinary anomaly spectrum described across the
    reported cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies (cryptorchidism, hypospadias, and vesicoureteral reflux), spondyloepiphyseal dysplasia, and other skeletal anomalies"
    explanation: Lists hypospadias within the genitourinary anomaly spectrum of the
      disorder.
- name: Vesicoureteral reflux
  category: Genitourinary
  description: >
    Vesicoureteral reflux, in at least one case requiring surgery, is part of the
    genitourinary spectrum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He underwent surgeries for vescicoureteral reflux and bilateral cryptorchidism."
    explanation: Documents vesicoureteral reflux requiring surgery in a reported patient.
- name: Retinal degeneration
  category: Ophthalmological
  description: >
    Retinal degeneration was present in all four boys carrying p.R32L and is
    proposed as a variant-specific clinical clue. Pathogenic variants in known
    inherited retinal degeneration genes were excluded in those probands.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to features consistent with RPL10-related disorder, all four boys had retinal degeneration and postnatal microcephaly."
    explanation: Documents retinal degeneration in all four p.R32L probands.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation"
    explanation: Records the proposed genotype-phenotype correlation limiting retinal
      involvement to p.R32L.
- name: Exotropia
  category: Ophthalmological
  description: >
    Exotropia and other strabismus are reported within the ophthalmological
    spectrum of the disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies"
    explanation: Lists exotropia among the features of the complex end of the spectrum.
- name: Hearing impairment
  category: Otological
  description: >
    Hearing loss is reported in the syndromic spectrum and is specifically
    associated with the p.K78E allele.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."
    explanation: Associates hearing loss with the recurrent p.K78E allele.
- name: Spondyloepiphyseal dysplasia
  category: Skeletal
  description: >
    Spondyloepiphyseal dysplasia was reported in the two cousins carrying p.A64V
    and established RPL10 as a new genetic cause of SED. RPL10 protein is highly
    expressed in vertebrate epiphyseal cartilage, giving a plausible basis for the
    skeletal involvement.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Spondyloepiphyseal dysplasia
    term:
      id: HP:0002655
      label: Spondyloepiphyseal dysplasia
  evidence:
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders."
    explanation: Establishes RPL10 as a cause of spondyloepiphyseal dysplasia.
- name: Laryngomalacia
  category: Respiratory
  description: >
    Laryngomalacia is part of the reported airway spectrum; congenital laryngeal
    stridor was present in both recently reported Chinese patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to a complex disease including growth retardation, microcephaly, seizures, exotropia, laryngomalacia, genitourinary anomalies"
    explanation: Lists laryngomalacia among the features of the complex end of the
      spectrum.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >
    Early feeding difficulty is reported in the neonatal period, alongside airway
    involvement and orofacial hypotonia.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also presented with feeding difficulties, congenital laryngeal stridor, neonatal pneumonia, and neonatal hypoglycemia."
    explanation: Documents feeding difficulties in the neonatal period.
- name: Mitral valve prolapse
  category: Cardiovascular
  description: >
    Cardiac involvement is variable. Mild mitral and tricuspid valve prolapse with
    regurgitation was found on echocardiography in two brothers carrying p.R32L,
    and cardiac defects are associated with the p.K78E allele. Attribution in the
    older brother is confounded: he also carries a pathogenic FBN1 variant
    (p.Arg1530Cys) with a Marfan systemic score of 4 and lens subluxation, and
    mitral valve prolapse is a cardinal Marfan feature. His brother had mitral
    prolapse with no reported FBN1 variant, so the finding is not wholly explained
    by Marfan syndrome, but this phenotype should not be attributed to RPL10 on
    the strength of that family alone.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac ultrasound showed mild mitral prolapse and tricuspid prolapse with regurgitation without aortic root dilatation."
    explanation: Documents echocardiographic mitral valve prolapse in a reported patient.
- name: Abnormal heart morphology
  category: Cardiovascular
  description: >
    Structural cardiac defects are reported in the syndromic spectrum and are
    specifically associated with the p.K78E allele. This is the broader
    structural claim; the separate Mitral valve prolapse entry records the one
    specific lesion described, along with the FBN1 confound attached to it.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features."
    explanation: Associates structural cardiac defects with the recurrent p.K78E allele.
- name: Polyhydramnios
  category: Prenatal
  description: >
    Excess amniotic fluid was present in 3 of 4 affected pregnancies in the
    Thevenon family, making it a recognised prenatal feature. No frequency is
    recorded here: the only quantification is 3 of 4 within one family, which is
    not a cohort rate, and no published series estimates one.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:25846674
    reference_title: RPL10 mutation segregating in a family with X-linked syndromic
      Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism"
    explanation: Reports amniotic fluid excess in 3 of 4 affected pregnancies.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >
    No population-based prevalence or incidence estimate exists. The literature
    quantifies the disorder only as a cumulative case count. Cappuccio et al.
    reviewed publications from 2006 to 2022 and retrieved 15 individuals with
    pathogenic RPL10 variants; Xu et al. counted 19 previously reported male
    patients carrying seven missense variants over 2014-2024. The two figures are
    the same cohort counted at different points, not a disagreement: Cappuccio's
    15 is the pre-existing literature, and their own total including the four new
    p.R32L probands is 19, which is the number Xu then carried forward. Reported
    patients come from Europe, North America and East Asia
    with no founder effect; the apparent geography reflects exome-sequencing
    access.
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemizygous pathogenic variants in RPL10 have been described in only 15 patients with a wide spectrum of manifestations"
    explanation: Gives the pre-existing literature count that Cappuccio started from.
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 19 males with RPL10‐related disorder, including the four individuals in the present study, are known so far."
    explanation: Gives the same paper's total including its four new probands, which
      is the 19 the later count carries forward.
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the past decade (2014∼2024), only seven missense RPL10 gene variants have been identified in the 19 previously reported male patients."
    explanation: Gives the updated cumulative case and allele count as of 2025.
diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >
    There are no formal clinical diagnostic criteria and the phenotype is not
    specific enough to be separated clinically from other X-linked intellectual
    disability, so molecular diagnosis is definitive. Every reported case was
    ascertained by exome sequencing, in most instances after a normal
    array-CGH and negative targeted testing (including fragile X). The trio design
    matters both for detecting the occasional de novo variant and for confirming
    maternal carrier status, which drives recurrence counselling. Most RPL10
    missense alleles are initially returned as variants of uncertain
    significance, so functional follow-up may be required for reclassification.

    The clinical differential is other syndromic X-linked intellectual disability
    of similar presentation, in particular MECP2, KDM5C, USP9X and MSL3. None is
    separable from MRXS35 on phenotype alone, which is why the diagnosis is
    molecular; a multi-gene panel or exome covers them together.

    Chromosomal microarray is not merely historical here. RPL10 sits inside the
    recurrent Xq28 duplication interval alongside FLNA and GDI1, and multigenic
    Xq28 copy-number gains produce their own intellectual disability syndromes
    that are distinct from MRXS35 and not attributable to RPL10. Microarray is
    what separates them from a point mutation in this gene.
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to their multiple congenital anomalies, whole-exome sequencing (WES) was recommended and conducted."
    explanation: Establishes exome sequencing as the diagnostic route in practice.
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Sanger sequencing also confirmed that the same hemizygous variant was derived from their respective heterozygous carrier mothers, and their respective fathers were normal."
    explanation: Shows the role of parental testing in confirming maternal carrier status.
treatments:
- name: Multidisciplinary Supportive and Developmental Care
  description: >
    There is no disease-modifying therapy, no approved drug, no gene therapy and
    no interventional clinical trial for MRXS35. Management is entirely
    symptomatic and supportive: early developmental intervention plus coordinated
    surveillance of growth, seizures, vision (including retinal assessment),
    hearing, cardiac structure, genitourinary anatomy and airway. Of the recently
    reported neonatal presentations, the hypoglycemia and the pneumonia are
    documented as transient and improving with routine management; no such course
    is reported for the laryngeal stridor or the feeding difficulty.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms of neonatal hypoglycemia and hypoglycemia (caused by bacteria) were transient, and both cases showed significant improvement with appropriate interventions."
    explanation: Documents that the neonatal complications respond to supportive management.
- name: Speech and Language Therapy
  description: >
    Speech delay is a hallmark feature and expressive language is
    disproportionately affected, with some individuals non-verbal into school age,
    so early speech therapy with augmentative and alternative communication where
    needed is a core intervention.
  treatment_term:
    preferred_term: Speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the last clinical evaluation at the age of 9 years, he was still non-verbal."
    explanation: Documents the persistent expressive language impairment this intervention
      targets.
- name: Physical Therapy and Motor Rehabilitation
  description: >
    Hypotonia, delayed independent walking and tiptoe gait are recurrent, and
    cerebellar involvement contributes to ataxia in a subset, so physiotherapy
    targeting tone, gait and mobility is standard.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the first months of life, he showed generalized hypotonia with severe orofacial hypotonia but normal deep tendon reflexes."
    explanation: Documents the generalized hypotonia this intervention targets.
- name: Occupational Therapy
  description: >
    Hypotonia, brachydactyly and clinodactyly, and the global developmental delay
    affect fine motor skill and daily function, so occupational therapy sits
    alongside physiotherapy and speech therapy in the standard developmental
    package. No RPL10-specific protocol exists.
  treatment_term:
    preferred_term: Occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40861044
    reference_title: 'Case Report: Identification of a novel hemizygous missense RPL10
      gene variant in two unrelated patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, the hallmark phenotypes of MRXS35 are intellectual disability, growth retardation, speech delay, microcephaly, craniofacial anomalies, seizures, hypotonia, and cryptorchidism."
    explanation: Names the developmental delay and hypotonia this intervention targets.
- name: Antiseizure Pharmacotherapy
  description: >
    Seizures are a core feature and may be refractory and early-onset, requiring
    antiseizure medication. No RPL10-specific antiseizure regimen has been
    established and no agent has been shown to be preferentially effective in
    this disorder, so treatment follows standard epilepsy practice for the
    observed seizure semiology.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29066376
    reference_title: 'A de novo mutation in RPL10 causes a rare X-linked ribosomopathy
      characterized by syndromic intellectual disability and epilepsy: A new case and
      review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder"
    explanation: Documents the refractory early-onset epilepsy that motivates antiseizure
      pharmacotherapy.
- name: Surgical Correction of Congenital Anomalies
  description: >
    Cryptorchidism (usually bilateral) and vesicoureteral reflux are the anomalies
    most often requiring operative management; adenoidectomy has been performed for
    obstructive sleep disorder.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:35876338
    reference_title: Postnatal microcephaly and retinal involvement expand the phenotype
      of RPL10-related disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He underwent surgeries for vescicoureteral reflux and bilateral cryptorchidism."
    explanation: Documents the surgical management of the two commonest genitourinary
      anomalies.
- name: Genetic Counseling and Carrier Testing
  description: >
    Transmission is usually from an unaffected heterozygous mother, so carrier
    testing of the mother and at-risk female relatives, with counselling on 50%
    transmission risk to sons, is central to management. Documented skewed X
    inactivation in carriers supports their unaffected status but does not
    guarantee it across the allelic series.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation"
    explanation: Establishes the maternal carrier transmission pattern that counselling
      addresses.
animal_models:
- name: rpl10 morpholino knockdown zebrafish
  species: Zebrafish
  genotype: rpl10 translation-blocking morpholino knockdown, with p.K78E mRNA complementation
  publication: PMID:25316788
  description: >
    Morpholino suppression of endogenous rpl10 in developing zebrafish embryos.
    The model was used both to establish that rpl10 loss produces a microcephaly-like
    phenotype and, by in vivo complementation, to test whether the human p.K78E
    allele retains function.
  evidence:
  - reference: PMID:25316788
    reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
      neurodevelopment and causes X-linked microcephaly in humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos"
    explanation: >-
      Establishes that this model is informative for the disorder: endogenous
      rpl10 is enriched in the anterior structures that the human phenotype
      affects, and its suppression reproduces the head-size deficit.
  modeled_mechanisms:
  - target: Increased Apoptosis and Impaired Proliferation in the Developing Brain
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >
      rpl10 suppression reduces bulk translation and increases apoptosis in the
      developing brain, reproducing the proposed cellular lesion.
    limitations: >
      Transient morpholino knockdown models complete loss of rpl10, whereas the
      human disorder is caused by hemizygous missense alleles that retain a
      protein product; morphant phenotypes are also susceptible to off-target
      effects not controlled by a genetic mutant in this study.
    readouts:
    - name: Brain apoptosis in morphant embryos
      target: Increased Apoptosis and Impaired Proliferation in the Developing Brain
      direction: INCREASED
      interpretation: Cellular correlate of the apoptosis node in this model.
      evidence:
      - reference: PMID:25316788
        reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
          neurodevelopment and causes X-linked microcephaly in humans.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain"
        explanation: Reports the apoptosis measurement behind this readout.
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish."
      explanation: Establishes the model as the system used to test this mechanism.
  - target: RPL10 Missense Substitution in uL16
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >
      In vivo complementation with human mRNA carrying p.K78E was used as the
      functional assay that classified the allele as loss of function.
    limitations: >
      The assay reports on rescue of a morphant phenotype in a fish embryo and does
      not measure the biochemical step (60S maturation) that the substitution is
      inferred to disrupt.
    evidence:
    - reference: PMID:25316788
      reference_title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts
        neurodevelopment and causes X-linked microcephaly in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant."
      explanation: States the complementation result that this model contributes.
discussions:
- discussion_id: ul16_maturation_checkpoint_untested_in_syndromic_alleles
  kind: KNOWLEDGE_GAP
  prompt: >
    Does the 60S maturation checkpoint failure demonstrated for uL16 in yeast
    actually occur in cells carrying the MRXS35 alleles?
  attaches_to:
  - pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation
  rationale: >
    The molecular step in this entry's central node - trapping of Nmd3 in the P
    site and failure to release Tif6 - has been demonstrated for the somatic
    leukemia allele rpl10-R98S in S. cerevisiae, not for any of the germline
    syndromic alleles. The MRXS35 alleles have been assayed only at coarser
    resolution: morphant rescue in zebrafish (p.K78E), transcript and protein
    level in transfected cells (p.R116Q), and polysome distribution in yeast
    (p.A64V). No study has measured Nmd3/Tif6 release, pre-60S quality control
    passage, or subunit joining for a syndromic allele. The chain from the
    initiating lesion to reduced translational capacity is therefore assembled
    from a conserved-protein argument rather than from direct measurement in this
    disease, and the evidence items on those edges are graded INDIRECT for that
    reason.
  evidence:
  - reference: PMID:28715419
    reference_title: The T-cell leukemia related rpl10-R98S mutant traps the 60S export
      adapter Nmd3 in the ribosomal P site in yeast.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Mutations in the ribosomal protein Rpl10 (uL16) can be drivers of T-cell acute lymphoblastic leukemia (T-ALL)."
    explanation: >-
      Establishes the gap: the allele in which this checkpoint defect was
      characterised is a leukemia driver, not one of the germline syndromic
      alleles this entry is about.
  proposed_experiments:
  - experiment_id: late_60s_maturation_assay_across_mrxs35_alleles
    name: Late 60S maturation assay across the MRXS35 allelic series
    description: >
      Reconstitute each syndromic RPL10 allele (p.R32L, p.A64V, p.K78E, p.R116Q)
      alongside p.R98S and wild type, and measure Nmd3 and Tif6 release,
      pre-60S cytoplasmic quality control passage, and 60S-40S subunit joining.
    would_support:
    - pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation
    supporting_outcome:
    - >-
      Syndromic alleles show retained Nmd3 and Tif6 on cytoplasmic pre-60S
      particles and reduced subunit joining relative to wild type.
    would_refute:
    - pathophysiology#Impaired Late Cytoplasmic 60S Subunit Maturation
    refuting_outcome:
    - >-
      Syndromic alleles release Nmd3 and Tif6 normally and join subunits at
      wild-type rates, indicating the neurodevelopmental alleles act through a
      mechanism other than the late maturation checkpoint.
- discussion_id: no_humanized_knock_in_mammalian_model
  kind: HUMAN_MODEL_MISMATCH
  prompt: >
    Does a mammalian model carrying a human MRXS35 allele reproduce the disorder,
    or is the whole mechanistic account resting on a transient fish knockdown?
  attaches_to:
  - animal_models#Zebrafish
  - pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain
  rationale: >
    The only in vivo model of this disorder is transient morpholino knockdown of
    rpl10 in zebrafish. That model suppresses the gene entirely, whereas every
    reported patient carries a hemizygous missense allele that still produces
    protein, so it models absence rather than substitution. Its one allele-specific
    result is a failed rescue, which shows p.K78E is loss of function but does not
    show what the mutant protein does. No knock-in mouse or other mammalian model
    carrying a human MRXS35 allele has been reported, so the cerebellar, retinal,
    skeletal and craniofacial features have no in vivo model at all, and the
    developmental timing of the microcephaly - postnatal in patients - cannot be
    studied in a fish embryo assay. This is a model-fidelity question rather than
    an absence of evidence, which is why it is filed as HUMAN_MODEL_MISMATCH.
  proposed_experiments:
  - experiment_id: humanized_knock_in_mouse_for_mrxs35_alleles
    name: Knock-in mouse carrying a human MRXS35 allele
    description: >
      Generate mice carrying the orthologous p.K78E and p.R32L substitutions and
      phenotype them for postnatal head growth, cerebellar development, retinal
      degeneration, skeletal morphology and seizure susceptibility, against the
      corresponding null allele as a comparator.
    would_support:
    - pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain
    supporting_outcome:
    - >-
      Knock-in mice reproduce postnatal microcephaly with reduced neural
      progenitor proliferation and increased apoptosis, and the allele-specific
      retinal and skeletal features track the alleles that carry them in patients.
    would_refute:
    - pathophysiology#Increased Apoptosis and Impaired Proliferation in the Developing Brain
    refuting_outcome:
    - >-
      Knock-in mice are unaffected, or show a phenotype only at null-allele dosage,
      indicating the zebrafish knockdown phenotype reflects gene loss rather than
      what the human missense alleles do.
- discussion_id: a64v_increased_translating_ribosomes_paradox
  kind: KNOWLEDGE_GAP
  prompt: >
    Why does p.A64V increase the actively translating ribosome population when a
    loss-of-function model predicts the opposite?
  attaches_to:
  - pathophysiology#p.A64V Increases the Actively Translating Ribosome Population
  - genetic#RPL10
  rationale: >
    The dominant mechanistic account of this disorder is loss of function, and two
    alleles support it. p.A64V does not: in yeast it complements a conditional
    lethal rpl10 mutation and shifts the polysome profile toward more actively
    translating ribosomes, yet the two cousins carrying it have intellectual
    disability, cerebellar hypoplasia and spondyloepiphyseal dysplasia. Either the
    disorder can arise from opposite directions of translational perturbation, or
    the yeast polysome readout does not capture the relevant human defect. This
    matters for interpretation of new missense alleles, which are routinely
    returned as variants of uncertain significance and adjudicated against a
    loss-of-function expectation.
  evidence:
  - reference: PMID:26290468
    reference_title: A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked
      Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10."
    explanation: >-
      Documents the observation that creates the gap: a pathogenic allele that
      nonetheless yields a functional protein, contradicting a uniform
      loss-of-function account.
  proposed_experiments:
  - experiment_id: a64v_vs_lof_in_human_neural_progenitors
    name: Human neural cell comparison of p.A64V against loss-of-function alleles
    description: >
      Introduce p.A64V and a demonstrated loss-of-function allele into isogenic
      human iPSC-derived neural progenitors and compare ribosome content, bulk
      translation rate, translational fidelity and the translated transcriptome.
    would_support:
    - pathophysiology#Reduced Pool of Translation-Competent 60S Subunits
    supporting_outcome:
    - >-
      p.A64V reduces ribosome content or bulk translation in human neural cells
      despite the opposite polysome result in yeast, reconciling it with the
      loss-of-function chain.
    would_refute:
    - pathophysiology#Reduced Pool of Translation-Competent 60S Subunits
    refuting_outcome:
    - >-
      p.A64V leaves ribosome content and bulk translation intact while altering
      which transcripts are translated, indicating a qualitative rather than
      quantitative translational lesion.

📚

References & Deep Research

References

3

PMID:25316788

A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans.

No top-level findings curated for this source.

PMID:35876338

Postnatal microcephaly and retinal involvement expand the phenotype of RPL10-related disorder.

No top-level findings curated for this source.

PMID:40861044

Case Report: Identification of a novel hemizygous missense RPL10 gene variant in two unrelated patients.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Address ai4c-reviewer changes-requested on PR #11322 (MRXS35) · 2026-09-07T08:52:04Z · View source

Third round on MRXS35, addressing the automated review on https://github.com/monarch-initiative/dismech/pull/11322 (ai4c-reviewer, REQUEST_CHANGES). One blocking finding and four non-blocking suggestions; all five taken in a single push, since branch protection dismisses the approval on every push. BLOCKING, and the reviewer was right. The a64v_increased_translating_ribosomes_paradox discussion still pointed at pathophysiology#Hypomorphic C-Terminal uL16 Variants Altering Translational Regulation. That was a defect introduced by the previous round: when the bundled node was split, the new p.A64V node was created but the discussion's attaches_to was never repointed, so a knowledge gap entirely about the N-terminal p.A64V allele hung off the node describing the C-terminal autism alleles. Nothing catches this automatically -- the foreign key resolves, so check-entity-refs passes and the page renders; it simply renders on the wrong branch of the allelic series, which is a substantive misstatement about which allele does what. Repointed to pathophysiology#p.A64V Increases the Actively Translating Ribosome Population. SUGGESTION 1 taken. Added an Abnormal heart morphology phenotype (HP:0001627) for the broader structural cardiac involvement associated with p.K78E, cited to PMID:29066376. The existing Mitral valve prolapse entry stays as the one specific lesion, keeping the FBN1/Marfan confound attached to the finding it actually qualifies rather than spreading it over the general cardiac claim. SUGGESTION 2 taken. Added an Occupational Therapy treatment (NCIT:C121351, therapeutic_modality BEHAVIORAL) targeting global developmental delay, completing the developmental package beside the existing physical and speech therapy entries. SUGGESTION 3 taken. Added the clinical differential (MECP2, KDM5C, USP9X, MSL3) to the diagnosis description, with the point that none is separable from MRXS35 on phenotype alone, which is why diagnosis is molecular. Written as description prose rather than as an evidence-bearing claim, because the differential comes from the deep-research report's synthesis and no cached reference carries a quotable sentence asserting it. SUGGESTION 4 taken, and filed as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP. The reviewer proposed a knowledge gap for the absent humanized knock-in mammalian model. The repository distinguishes the two kinds: KNOWLEDGE_GAP means evidence is absent, HUMAN_MODEL_MISMATCH means evidence exists in a model whose translational validity is the open question. That is the situation here -- a zebrafish morphant model exists and is cited throughout, but it suppresses the gene entirely while every patient carries a missense allele that still makes protein, so it models absence rather than substitution. The gap attaches to the zebrafish model and to the apoptosis/proliferation node, and proposes a knock-in mouse carrying the orthologous p.K78E and p.R32L substitutions. NOT ACTED ON. The reviewer disclosed two checks it could not run for lack of network access: independent PubMed verification of the 11 PMIDs, and the GeneReviews existence check. Both were performed during the original curation session against live NCBI E-utilities. Every PMID was fetched through just fetch-reference, which resolves against PubMed, and the GeneReviews search ('RPL10 GeneReviews[All Fields]' plus a title search) returned zero results, which is recorded in the first history record for this entry. No further action is needed; the checks are done, just not by the reviewer. Validation after this round: just validate and just validate-disorders pass, 83/83 snippets verified, compliance 91.2% global / 91.6% weighted (198 of 217 satisfied slots, up from 191; the ratio moves down because the added nodes enlarge the denominator faster than they fill it). Pathograph 43 nodes / 27 edges, zero orphan targets. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-grading, check-title-snippets and check-snippet-length all clean.

Create: Intellectual Disability X-linked Syndromic 35 (MRXS35, RPL10) · 2026-09-07T03:51:42Z · View source

De novo curation of MRXS35 (MONDO:0030908; RPL10/uL16, Xq28) from an empty stub. DEEP RESEARCH. falcon was the requested provider and could not run: the Edison account returned HTTP 402 (out of credits) on two attempts. Rather than substituting a provider by hand, the run was re-issued with dr_fallback='--fallback', so openscientist produced the report and the substitution is recorded in the report frontmatter (fell_back: true, requested_provider: falcon, provider_attempts). Report: research/Intellectual_Disability_X-linked_Syndromic_35-deep-research-openscientist.md (980s, 12 citations). REPORT VALIDATION READ BEFORE USE. needs_review: true. Reference validation: 12/12 resolved, 0 not found, confabulation_rate 0.0; one reference (PMID:30482776, 'Ribosomal Lesions Promote Oncogenic Mutagenesis') flagged off topic — it is a T-ALL somatic-oncogenesis paper and was not cited. Term validation: 34/36 resolved, 0 unresolved, but 8 terms reported as mislabelled. On inspection all 8 are the report placing a frequency word ('Frequent', 'Subset') in its table's label column; the CURIEs themselves (HP:0001999, HP:0001250, HP:0000717, HP:0001561, HP:0004322, HP:0000546, HP:0000365) match the bindings independently chosen here, so they are a report formatting artifact rather than wrong bindings. No term listed as unresolved was bound. just preflight-dr PASSED (RPL10 mentioned 54 times; OMIM 300998 matches). GENEREVIEWS. Searched PubMed for a GeneReviews chapter on RPL10/MRXS35 ('RPL10 GeneReviews[All Fields]' and title search): zero results. No chapter exists, so no GeneReviews baseline applies. Step 3b recorded as not applicable rather than skipped. CITATIONS. 11 references, all PMIDs (no DOI-only items), all fetched via just fetch-reference and committed to references_cache/. Eight came from the report's citation list; three were found independently by PubMed E-utilities search because the report did not cite them and they carry content the entry needed: PMID:26290468 (Zanni, the p.A64V / cerebellar hypoplasia / spondyloepiphyseal dysplasia family), PMID:28715419 and PMID:24706786 (the uL16 late-60S-maturation checkpoint biochemistry). CITATIONS DELIBERATELY NOT USED. Five of the report's twelve were rejected on substance, not availability. PMID:31090057 and PMID:20004760 are Xq28 *duplication* syndromes (MECP2/MidXq28 region) — a different disorder that shares only the cytogenetic band with RPL10, and citing them would be exactly the Named Entity Confusion the preflight guards against. PMID:28744013, PMID:31186416 and PMID:30482776 are somatic T-ALL RPL10-R98S papers (JAK-STAT gain of activity, serine/glycine translatome, oncogenic mutagenesis); that is a mechanistically distinct somatic disease and importing it would misrepresent the germline disorder. HANDLING OF THE LEUKEMIA-ALLELE MECHANISM PAPERS. Two yeast rpl10-R98S papers (PMID:28715419, PMID:24706786) ARE cited, but only to establish the conserved biochemistry of uL16 in late cytoplasmic 60S maturation (Nmd3/Tif6 release), never as evidence about MRXS35 patients. Every such item is graded directness: INDIRECT with an explanation naming the limitation, the entry's description carries an explicit scope note separating the germline disorder from the somatic T-ALL context, and a KNOWLEDGE_GAP discussion records that the checkpoint defect has never been measured for any syndromic allele. PMID:9443083 (QM protein, the original name for RPL10) was added from the report to anchor the same step in human cells rather than yeast alone. CONTENT. 6-node causal pathophysiology chain from the missense lesion through failed late 60S maturation, a reduced translation-competent subunit pool, neural apoptosis, to impaired brain growth, plus a separate node for the hypomorphic C-terminal autism alleles that does not proceed through that chain. 22 phenotypes with HP bindings, genetic (RPL10, hgnc:10298) with genetic_context on the initiating node, X-linked recessive inheritance, diagnosis, prevalence (CASES_IN_LITERATURE; the 15 vs 19 published-case discrepancy between Cappuccio 2022 and Xu 2025 is recorded and explained rather than averaged), 6 treatments with NCIT bindings, a zebrafish morphant animal model with two modeled_mechanisms links and a readout, and two KNOWLEDGE_GAP discussions with proposed experiments. gnomAD constraint values are recorded in genetic notes rather than as an evidence item, because they are database statistics with no quotable source sentence. VALIDATION. just validate passed (schema, terms, references). 68/68 snippets verified against the local cache. just validate-disorders (the batched pre-PR gate CI runs) passed. just compliance 95.5% global / 96.0% weighted. Offline gates run clean: check-entity-refs, check-causal-targets (no new dangling targets), check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-grading, check-title-snippets, check-snippet-length. The curated stub stubs/Intellectual_Disability_X-linked_Syndromic_35.yaml was deleted and just check-stubs passes.

OpenScientist ▸

Key Findings

openscientist-autonomous 12 citations 2026-09-07T03:07:31.470112

Key Findings

Finding 1 — MRXS35 is caused by hemizygous missense variants in RPL10 (uL16), an X-linked ribosomopathy

MRXS35 (OMIM #300998) is caused by hemizygous missense variants in RPL10 (HGNC:10298; Entrez Gene 6134; Ensembl ENSG00000147403; gene-MIM 312173; cytoband Xq28; aliases QM, uL16, AUTSX5, L10, DXS648, NOV). The gene was first implicated in neurodevelopmental disease through autism families, where two C-terminal missense substitutions (p.L206M and p.H213Q) were identified: "We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism" (PMID: 16940977). The syndromic microcephaly/ID phenotype was subsequently defined by the identification of "a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10)" — the p.K78E allele (PMID: 25316788).

The recurrent pathogenic missense alleles map to functionally critical regions of the protein. The N-terminal variants (p.R32L, p.K78E) fall within the 28S/25S rRNA-binding region near the peptidyl transferase center, while p.L206M and p.H213Q lie in the C-terminal region. Inheritance follows an X-linked recessive paradigm: "the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation" (PMID: 25316788). The normal molecular role of the protein — it is "required for the joining of the 40S and 60S subunits" (PMID: 9443083) — anchors the ribosomopathy mechanism. Zebrafish complementation established that p.K78E is a loss-of-function allele.

Ontology anchors: Gene HGNC:10298 (RPL10); disease MONDO:0030908; GO:0022618 (ribonucleoprotein complex assembly), GO:0042254 (ribosome biogenesis), GO:0006412 (translation).

Finding 2 — RPL10 is highly intolerant to loss-of-function and missense variation

Population constraint metrics from gnomAD confirm that RPL10 is under strong purifying selection, consistent with an essential housekeeping gene. gnomAD v2 constraint values for ENSG00000147403 are: pLI = 0.997 (loss-of-function intolerant), observed/expected LoF = 0.064 (1 observed vs. 15.7 expected; LOEUF/oe_lof_upper = 0.30), LoF-Z = 3.15, and missense-Z = 4.08 (oe_mis = 0.29), while the synonymous-Z of 0.37 confirms the model is well-calibrated (neutral for silent variation). The gene spans chrX:154,389,955–154,409,168 (GRCh38), Xq28.

The practical consequence is that pathogenic RPL10 missense variants are essentially absent from population reference databases: for one reported pathogenic allele, the "variant, not reported in gnomAD" (PMID: 35876338). This strong constraint supports ACMG criterion PM2 (absent/rare in population databases) for candidate variants and explains why only hypomorphic (partial loss-of-function) missense alleles — rather than complete null alleles — are compatible with viability and thus observed in patients.

Constraint metric (gnomAD v2)	Value	Interpretation
pLI	0.997	LoF-intolerant
oe LoF (LOEUF)	0.064 (0.30)	Strong LoF depletion
LoF-Z	3.15	Significant constraint
Missense-Z	4.08	Strong missense constraint
Synonymous-Z	0.37	Neutral (calibrated)

Finding 3 — Clinical spectrum: syndromic ID with epilepsy, ASD, microcephaly, dysmorphism, and congenital anomalies

Across ~15–19 reported affected males, the core phenotype comprises intellectual disability/developmental delay (near-universal; 4/4 in the Thevenon 2015 family), autism spectrum disorder, epilepsy (often early-onset, refractory seizures), and facial dysmorphism. MRXS35 is defined as "an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies" (PMID: 35876338).

Microcephaly occurs in approximately half of cases and is often progressive/postnatal: "microcephaly was observed in approximately half of the cases" (PMID: 35876338). A family segregating an RPL10 variant showed a characteristic combination of "syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism" (PMID: 25846674), documenting per-feature frequencies. The severe end of the spectrum, associated with p.K78E, includes "severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features" (PMID: 29066376).

Certain features are variant-associated: retinal degeneration/retinitis pigmentosa is notable with p.R32L, while severe multisystem involvement (hearing loss, cardiac defects) clusters with p.K78E. Onset spans the prenatal/neonatal period (polyhydramnios) to early childhood, and both microcephaly and retinopathy can be progressive.

Phenotype	Approx. frequency	Suggested HPO term
Intellectual disability / developmental delay	Near-universal	HP:0001249 / HP:0001263
Facial dysmorphism	Very frequent	HP:0001999
Microcephaly (often progressive/postnatal)	~50%	HP:0000252 / HP:0005484
Epilepsy / seizures	Frequent	HP:0001250
Autism spectrum disorder	Frequent	HP:0000717
Cerebellar signs / ataxia	~50% (2/4)	HP:0001251
Urogenital/genital anomalies (incl. cryptorchidism)	Frequent (3/4)	HP:0000078 / HP:0000028
Polyhydramnios (antenatal)	Frequent (3/4)	HP:0001561
Short stature / growth retardation	Frequent	HP:0004322
Hypotonia	Reported	HP:0001252
Retinal degeneration (variant-associated, p.R32L)	Subset	HP:0000546
Hearing loss (variant-associated, p.K78E)	Subset	HP:0000365
Cardiac defects (variant-associated, p.K78E)	Subset	HP:0001627

Finding 4 — Mechanism: germline hypomorphic variants impair translation and increase apoptosis; distinct somatic R98S drives leukemia

The germline (MRXS35) mechanism is a partial loss of ribosomal function. In a zebrafish model, rpl10 suppression "decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain" (PMID: 25316788); this phenotype is rescued by wild-type but not mutant human RPL10, establishing p.K78E as loss-of-function. Because uL16 "is required for the joining of the 40S and 60S subunits" (PMID: 9443083) and is added late during cytoplasmic 60S maturation, reduced functional protein throttles the supply of translation-competent ribosomes precisely when developing neurons demand high protein synthesis — leading to reduced neuronal output, apoptosis, and microcephaly.

Critically, the same gene harbors a mechanistically distinct somatic lesion in cancer. The recurrent p.R98S mutation occurs in ~8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL): "the recurrent RPL10-R98S mutation in T-cell acute lymphoblastic leukemia (T-ALL)" (PMID: 30482776). Rather than simple loss of function, R98S produces a gain of oncogenic activity — "we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation" (PMID: 28744013) — via reduced JAK1 degradation and altered programmed ribosomal frameshifting. R98S also induces oxidative stress (an early proliferation defect), upregulates serine biosynthesis (PSPH) and glycine (PMID: 31186416), and promotes secondary oncogenic mutagenesis including NOTCH1-activating lesions (PMID: 30482776). This germline-vs-somatic contrast underscores that RPL10 genotype–phenotype relationships are allele-specific and mechanism-specific.

Finding 5 — RPL10/uL16 protein: 214-aa cytoplasmic large-subunit ribosomal protein with resolved structures

The protein product is UniProt P27635 (human RPL10/uL16): 214 amino acids, cytoplasmic. UniProt annotation states it is a "Component of the large ribosomal subunit… Plays a role in the formation of actively translating ribosomes… May play a role in the embryonic brain development." At least 37 experimental PDB entries resolve uL16 within the human 80S ribosome (e.g., 5AJ0, 6OLE, 6OLF, 6OLG, 6OLI, 6OLZ), providing structural context for pathogenic residues. The MRXS35 residues Arg32, Lys78, Leu206, and His213 localize to rRNA-binding/N-terminal and C-terminal regions of the protein, and the protein sits in "close proximity to the peptidyl transferase active site of the 60S ribosomal subunit" (PMID: 25316788). This structural proximity to the catalytic center provides a plausible structural rationale for how single missense substitutions perturb translation.

Subcellular localization (GO Cellular Component): GO:0022625 (cytosolic large ribosomal subunit), GO:0005737 (cytoplasm), GO:0005840 (ribosome).

Finding 6 — ClinVar landscape and cross-species orthologs

ClinVar (RefSeq NM_006013.5) holds ~404 RPL10 records. At the single-nucleotide level, most missense variants are classified as variants of uncertain significance (VUS) (e.g., p.Leu36Gln, p.Asp44Tyr, p.Arg32Cys, p.Ile167Val), with a smaller set of Pathogenic/Likely-pathogenic SNVs corresponding to the known MRXS35 alleles. Importantly, many ClinVar entries labeled "Pathogenic" as copy-number gains/losses are large multigenic Xq deletions/duplications that span RPL10 rather than RPL10-specific point mutations — a distinction that matters for interpretation. The disease-relevant residues are "affecting an evolutionary conserved residue" (PMID: 35876338), consistent with strong cross-species conservation.

Validated orthologs supporting model-organism work: mouse Rpl10 (NCBI Gene 110954; MGI:105943; ENSMUSG00000008682); zebrafish rpl10 (NCBI Gene 336712); S. cerevisiae RPL10. Human RPL10 = NCBI Gene 6134, UniProt P27635 (214 aa).

Finding 7 — Novel p.Arg116Gln allele expands genotype, phenotype, and functional evidence

A 2025 report identified a novel recurrent hemizygous missense variant, NM_006013.5:c.347G>A, p.Arg116Gln, in two unrelated Chinese male patients, each maternally inherited: "the same hemizygous missense RPL10 gene variant (NM_006013.5:c.347G>A, p.Arg116Gln) in each patient, inherited from their respective mothers" (PMID: 40861044). In vitro functional analysis provided independent loss-of-function evidence: the variant "reduced the mRNA expression of the RPL10 gene, thereby decreasing synthesis of the RPL10 protein" (PMID: 40861044).

This report also expanded the neonatal/early phenotype to include "congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism" (PMID: 40861044), along with short stature, hypotonia, gastrointestinal problems, and craniofacial anomalies. The summarized full MRXS35 spectrum from this paper — ID, psychomotor/speech delay, short stature, craniofacial anomalies, hypotonia, seizures, GI problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss — reinforces the multisystem, prenatal-to-childhood nature of the disorder.

Section-by-Section Report

1. Disease Information

MRXS35 is an ultra-rare, X-linked recessive syndromic intellectual disability disorder — a ribosomopathy — caused by variants in RPL10. Key identifiers: OMIM #300998; MONDO:0030908; gene-MIM 312173 (RPL10). ICD-11 would fall under 6A00 (Disorders of intellectual development) with a genetic modifier; a specific Orphanet number is not firmly assigned in the retrieved data (the disorder overlaps the "RPL10-related disorder" concept). Common synonyms/alternative names: MRXS35; RPL10-related disorder; X-linked intellectual disability, syndromic, 35; historically linked to AUTSX5 (autism, X-linked 5) via the same gene. The information in this report is derived from aggregated disease-level resources (OMIM, ClinVar, gnomAD, UniProt, PDB) and individual patient case reports/series in primary literature, not from EHR-scale patient data.

2. Etiology

Causal factor: monogenic — hemizygous hypomorphic missense variants in RPL10 (Xq28). Genetic risk factors: the causal variants themselves (p.K78E, p.R32L, p.R116Q, p.L206M, p.H213Q); being male (hemizygous) is the principal determinant of clinical expression. Environmental risk factors: none established — this is a Mendelian disorder without a recognized environmental contribution. Protective factors: in carrier females, skewed X-inactivation favoring the wild-type allele is effectively protective, explaining why carrier mothers are typically unaffected. No dietary/lifestyle protective factors are known. Gene–environment interactions: none documented; disease liability is essentially determined by genotype and X-inactivation status.

3. Phenotypes

See Finding 3 table for phenotype types, frequencies, and HPO terms. Phenotype characteristics: onset is prenatal/neonatal (polyhydramnios, feeding difficulties, laryngeal stridor, neonatal hypoglycemia) to early childhood (developmental delay, seizures); severity is variable and partly genotype-dependent (p.K78E severe; C-terminal autism alleles milder/behavioral); progression is largely stable for ID but progressive for postnatal microcephaly and retinopathy. Quality-of-life impact is substantial where ID is moderate-to-severe, with lifelong dependency, communication impairment, and comorbid epilepsy and behavioral (ASD) burden; formal EQ-5D/SF-36 data are not available for this ultra-rare disorder.

4. Genetic/Molecular Information

Causal gene: RPL10 (HGNC:10298; NCBI 6134; gene-MIM 312173; Xq28). Pathogenic variants (germline): p.K78E (c.232A>G), p.R32L (c.95G>T), p.R116Q (c.347G>A), p.L206M, p.H213Q — all missense, all in the RefSeq NM_006013.5 transcript. Classification: the recurrent disease alleles are Pathogenic/Likely-pathogenic; the broader ClinVar landscape is VUS-dominant (Finding 6). Allele frequency: absent/ultra-rare in gnomAD (Finding 2). Origin: germline; typically maternally inherited from carriers with skewed X-inactivation, with de novo cases reported. Functional consequence: loss/reduction of function (hypomorphic), demonstrated in zebrafish (p.K78E) and by reduced mRNA/protein for p.R116Q. Modifier factors: X-inactivation pattern is the principal modifier in carrier females. Chromosomal abnormalities: large Xq28 copy-number gains/losses spanning RPL10 exist (e.g., MidXq28-duplication syndrome involving FLNA, RPL10, GDI1; and dosage-dependent Xq28 gains where GDI1 is the likelier driver — PMID: 31090057, PMID: 20004760), but these multigenic CNVs are distinct from RPL10 point-mutation MRXS35. Epigenetics: no disease-specific methylation signature established.

5. Environmental Information

Not applicable. MRXS35 is a monogenic disorder; no environmental toxins, lifestyle factors, or infectious agents are implicated in causation or triggering.

6. Mechanism / Pathophysiology

Ordered causal chain (germline MRXS35):

A hemizygous hypomorphic missense variant in RPL10 (e.g., p.K78E, p.R116Q) results in a structurally/functionally impaired uL16 protein (or reduced protein level, as shown for p.R116Q).
Reduced functional uL16 leads to impaired late cytoplasmic 60S maturation and defective 40S–60S subunit joining (uL16 is "required for the joining of the 40S and 60S subunits").
Defective subunit joining results in a reduced pool of actively translating 80S ribosomes and decreased bulk protein synthesis (demonstrated in zebrafish morphants).
Reduced translation in the developing brain leads to increased neuronal apoptosis and reduced neuronal output (demonstrated).
Neuronal loss/reduced proliferation results in reduced brain growth → microcephaly (often postnatal/progressive) and disrupted neurodevelopment → intellectual disability, autism, epilepsy (mechanism inferred from the translation-apoptosis link; clinical correlation strong).
Branch: tissue-specific translational vulnerability leads to variant-associated congenital anomalies — retinal degeneration (p.R32L), hearing loss/cardiac defects (p.K78E), and genitourinary/GI anomalies (inferred).

Pathways/processes: cytoplasmic translation (GO:0006412), ribosomal large subunit assembly/biogenesis (GO:0000027, GO:0042273), apoptotic process (GO:0006915), embryonic brain development. Protein dysfunction: partial loss of function of a ribosomal structural protein near the peptidyl transferase center. Cell types (CL): neurons (CL:0000540), neural progenitor/neuroblast (CL:0000031), and photoreceptor/cochlear/cardiac cells in variant-specific branches. This contrasts with the somatic T-ALL mechanism (p.R98S → JAK-STAT gain-of-function, serine/glycine metabolic rewiring, oncogenic mutagenesis; Finding 4).

7. Anatomical Structures Affected

Primary organ: brain (UBERON:0000955), especially cerebrum and cerebellum (UBERON:0002037; cerebellar signs). Body system: central nervous system (UBERON:0001017). Secondary/variant-associated: eye/retina (UBERON:0000970 / UBERON:0000966; retinal degeneration), ear/cochlea (hearing loss), heart (UBERON:0000948; cardiac defects), genitourinary tract (cryptorchidism), gastrointestinal tract, and larynx (congenital stridor). Tissue/cell level: nervous tissue; neurons and neural progenitors. Subcellular: cytoplasm/cytosolic ribosome (GO:0022625). Lateralization: bilateral/symmetric involvement (microcephaly, retinopathy, cryptorchidism when bilateral).

8. Temporal Development

Onset: congenital to early childhood; antenatal signs (polyhydramnios) and neonatal features (feeding difficulty, stridor, hypoglycemia) can precede developmental delay. Onset pattern: chronic/insidious for neurodevelopment; microcephaly frequently postnatal and progressive. Progression: intellectual disability is generally stable (non-degenerative), but head circumference and retinal findings can worsen over time. Course: chronic, lifelong. Critical period: the fetal/early-postnatal window of maximal neurogenesis and neuronal protein-synthesis demand is the period of greatest vulnerability and the theoretical window for intervention.

9. Inheritance and Population

Inheritance: X-linked recessive; affected males, unaffected carrier mothers with skewed X-inactivation; de novo cases reported. Penetrance: high/complete in hemizygous males; carrier females usually unaffected due to favorable X-inactivation (rare manifesting carriers possible). Expressivity: variable, partly genotype-dependent. Epidemiology: ultra-rare; fewer than ~20 well-characterized males reported worldwide; precise prevalence/incidence are not established. Sex ratio: strongly male-predominant. Founder effects/consanguinity: none established; the p.R116Q allele recurred in two unrelated Chinese families (recurrent mutation, not proven founder). Carrier frequency: not defined (variants absent from gnomAD).

10. Diagnostics

Diagnosis is molecular. Recommended approach: whole-exome sequencing (WES) or whole-genome sequencing (WGS), or a targeted intellectual disability/XLID gene panel including RPL10; single-gene testing is appropriate when a familial variant is known. Chromosomal microarray (CMA) is indicated to detect Xq28 CNVs in the differential (MidXq28-duplication syndrome). Variant interpretation follows ACMG/AMP guidelines: absence from gnomAD (PM2), evolutionary conservation, and functional/segregation evidence support pathogenicity; many RPL10 missense variants remain VUS. Supportive workup: brain MRI (microcephaly, cerebellar/structural findings), EEG (epilepsy), ophthalmologic exam (retinopathy), audiology, echocardiography, and growth/endocrine and metabolic evaluation (neonatal hypoglycemia). No specific biochemical biomarker exists. Differential diagnosis: other X-linked syndromic IDs (e.g., MECP2-related, KDM5C/Claes-Jensen, USP9X-related, MSL3/Basilicata-Akhtar) and other ribosomopathies. Screening: cascade carrier testing in families once the variant is identified; prenatal/preimplantation testing possible for known familial variants. No newborn-screening program exists.

11. Outcome/Prognosis

Survival: the disorder is chronic and non-malignant; life expectancy depends on severity of epilepsy and congenital anomalies (severe p.K78E cases with cardiac defects carry higher risk). No formal survival statistics are available. Morbidity: dominated by lifelong intellectual disability, communication impairment, epilepsy, and behavioral (ASD) burden, with additional disability from sensory (visual, auditory) and motor (hypotonia, cerebellar) involvement. Complications: refractory seizures, feeding difficulties/aspiration, growth failure, and organ-specific issues. Recovery: no reversal; management is supportive. Prognostic factors: specific genotype (p.K78E severe end), presence of epilepsy, degree of microcephaly, and multi-organ involvement.

12. Treatment

There is no disease-modifying or gene-specific therapy. Management is supportive and multidisciplinary (suggested NCIT: Supportive Care Intervention): - Antiepileptic pharmacotherapy for seizures (agent selection by seizure type; NCIT: Anticonvulsant Agent). - Developmental and rehabilitative therapies — physical, occupational, and speech therapy; special education. - Surveillance and management of ophthalmologic (retinopathy), audiologic (hearing loss, hearing aids), cardiac (congenital defect management), genitourinary (cryptorchidism — orchidopexy), and gastrointestinal/feeding complications. - Nutritional support for feeding difficulties and growth failure.

No pharmacogenomic guidance, gene therapy, cell therapy, RNA-based therapy, or targeted/immunotherapy is currently available or in trials for MRXS35 (no NCT identifiers retrieved). Personalized/precision approaches remain theoretical.

13. Prevention

Primary prevention is not possible for a spontaneous/inherited Mendelian variant. Secondary/tertiary prevention centers on early molecular diagnosis, early developmental intervention, and surveillance to prevent complications (e.g., seizure control, visual/hearing rehabilitation). Genetic counseling is central: for carrier mothers, recurrence risk is 50% for sons (affected) and 50% for daughters (carriers). Reproductive options include prenatal diagnosis and preimplantation genetic testing for known familial variants, and cascade testing of at-risk female relatives. No immunization, public-health, or environmental interventions apply.

14. Other Species / Natural Disease

RPL10 is highly evolutionarily conserved. Orthologs: mouse Rpl10 (NCBI 110954; MGI:105943; ENSMUSG00000008682); zebrafish rpl10 (NCBI 336712); S. cerevisiae RPL10. No naturally occurring companion-animal or wildlife disease equivalent to MRXS35 is documented in the retrieved data (no OMIA entry established here). Conservation of uL16's role in subunit joining across yeast, fish, and mammals underpins the validity of cross-species functional modeling. No zoonotic or cross-species transmission is relevant (non-infectious genetic disorder).

15. Model Organisms

The principal disease model is the zebrafish (Danio rerio): morpholino knockdown of rpl10 reproduces reduced head size, decreased bulk translation, and increased brain apoptosis; complementation (rescue) assays with wild-type vs. mutant human RPL10 established loss-of-function for p.K78E (PMID: 25316788). This model recapitulates the core microcephaly phenotype and directly demonstrates the translation–apoptosis mechanism. Yeast (S. cerevisiae) provided foundational evidence that QM/uL16 assembles onto the 60S subunit in the cytoplasm and is required for subunit joining (PMID: 9443083). A validated mouse ortholog exists (MGI:105943) and would be the natural system for a conditional/knock-in model, though a published MRXS35-specific mouse model was not identified. Limitations: morphant models capture microcephaly/translation defects but not the full multisystem, behavioral (ASD/epilepsy), or progressive retinal spectrum; humanized knock-in mammalian models are a key gap.

Mechanistic Model / Interpretation

   RPL10 hypomorphic missense variant (e.g., p.K78E, p.R116Q, p.R32L)
          │
          ▼
   Impaired / reduced uL16 protein (loss-of-function; near PTC)
          │
          ▼
   Defective late 60S maturation → impaired 40S–60S subunit joining
          │
          ▼
   Fewer actively translating 80S ribosomes → ↓ bulk protein synthesis
          │
     ┌────────────┴─────────────┐
     ▼                          ▼
   ↑ neuronal apoptosis          reduced neuronal output/proliferation
     │                          │
     └────────────┬─────────────┘
          ▼
 Reduced brain growth  →  MICROCEPHALY (progressive)
 Disrupted neurodevelopment → ID, ASD, EPILEPSY, cerebellar signs
          │
          ▼ (tissue-specific translational vulnerability — branch)
   Retinal degeneration (p.R32L) · Hearing loss + cardiac defects (p.K78E)
   Genitourinary / GI / laryngeal anomalies · Growth failure

   ─────────────────────────────────────────────────────────────
   CONTRAST — same gene, different disease:
   SOMATIC RPL10 p.R98S (T-ALL, ~8%) → JAK-STAT gain-of-function,
   ↑ serine/glycine biosynthesis (PSPH), oncogenic mutagenesis (NOTCH1)

The unifying principle is dosage-sensitive translational insufficiency in a highly constrained ribosomal protein: because RPL10 is LoF-intolerant (pLI 0.997), only partial (hypomorphic) missense alleles are compatible with survival, and their effect manifests most severely in the high-translation-demand developing brain. The germline (hypomorphic, developmental) and somatic (R98S, oncogenic gain-of-function) diseases are cleanly dissociable — a valuable illustration of allele- and context-specific pathobiology.

Evidence Base

PMID	Title (abbrev.)	Role	Evidence type
25316788	Novel ribosomopathy caused by dysfunction of RPL10… X-linked microcephaly	Defines gene, XLR inheritance, LoF mechanism (zebrafish)	Human + model organism
16940977	Mutations in RPL10 suggest a novel disease mechanism for autism	Original RPL10 identification (L206M, H213Q)	Human clinical
9443083	Assembly of the QM protein onto the 60S subunit… cytoplasm	Normal uL16 function (subunit joining)	In vitro / yeast
35876338	Postnatal microcephaly and retinal involvement expand phenotype	Phenotype spectrum, ~50% microcephaly, conservation, gnomAD-absent	Human clinical
25846674	RPL10 mutation segregating in family with XLID	Per-feature frequencies in affected family	Human clinical
29066376	De novo RPL10 mutation… syndromic ID and epilepsy	Severe end (p.K78E) phenotype; review	Human clinical
40861044	Novel hemizygous missense RPL10 (p.R116Q)	New allele, maternal inheritance, in vitro LoF, expanded neonatal features	Human + in vitro
28744013	RPL10 R98S enhances JAK-STAT signaling	Distinct somatic oncogenic mechanism	Model / in vitro
30482776	Ribosomal lesions promote oncogenic mutagenesis	R98S recurrent in T-ALL; secondary mutagenesis	Model / in vitro
31186416	Altered serine and glycine metabolism in T-ALL	R98S metabolic rewiring (PSPH)	Model / in vitro
31090057	MidXq28-duplication syndrome	Multigenic Xq28 CNV context (FLNA, RPL10, GDI1)	Human clinical
20004760	Dosage-dependent Xq28 copy-number gain	GDI1 dosage as likelier CNV driver; skewed XCI	Human clinical

Reference databases used: OMIM (#300998, gene-MIM 312173), gnomAD v2 (constraint), UniProt P27635, PDB (≥37 human 80S ribosome structures), ClinVar (~404 records, NM_006013.5), NCBI Gene / Ensembl / HGNC, and MGI/ZFIN (orthologs).

Limitations and Knowledge Gaps

Small N. Fewer than ~20 molecularly confirmed males limit precise frequency estimates, genotype–phenotype correlation, and epidemiology (no reliable prevalence/incidence).
VUS-dominant variant landscape. Most RPL10 missense variants in ClinVar are VUS; functional assays exist for only a few alleles (p.K78E, p.R116Q), so many candidate variants cannot be confidently classified.
Mechanistic gaps. The steps from reduced translation to specific clinical features (epilepsy, ASD, retinopathy, cardiac/GU anomalies) are largely inferred, not directly demonstrated in human neurons or organoids; the basis for tissue- and allele-specific involvement is unresolved.
No mammalian disease model. Published evidence rests on zebrafish morphants and yeast; a humanized knock-in mouse recapitulating the full syndrome is absent.
No natural-history or quality-of-life data, no biomarkers, and no therapeutic development specific to MRXS35.
CNV vs point-mutation ambiguity. Xq28 CNVs spanning RPL10 involve multiple candidate genes (GDI1, FLNA), complicating attribution to RPL10 itself.

Proposed Follow-up Experiments / Actions

Establish a humanized knock-in mouse or human iPSC-derived neuron/organoid model carrying p.K78E and p.R116Q to directly test the translation→apoptosis→microcephaly chain and dissect cell-type-specific vulnerability (neurons, photoreceptors, cardiomyocytes).
Systematic functional assays (subunit-joining, polysome profiling, ribosome footprinting) across all reported and VUS alleles to reclassify VUS and build a genotype–severity map — strengthening ACMG PS3 evidence.
International patient registry / natural-history study to quantify per-phenotype frequencies, onset, progression (especially microcephaly and retinopathy), survival, and quality of life.
Translatome/single-cell profiling of patient-derived neurons to identify the specific mRNAs whose translation is most sensitive to uL16 loss — candidate downstream effectors and biomarkers.
Structural analysis (cryo-EM/AlphaFold) mapping Arg32, Lys78, Arg116, Leu206, His213 onto the human 80S ribosome to model how each substitution perturbs rRNA binding and subunit joining.
Explore translation-modulating or apoptosis-limiting therapeutic strategies in the zebrafish/organoid models as proof-of-concept, given the absence of any disease-modifying therapy.

Report compiled from 5 completed investigation iterations, 7 confirmed findings, and 19 reviewed papers. Evidence types are distinguished as human clinical, model organism, in vitro, and computational throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	7
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:30482776 (6 mentions) - Ribosomal Lesions Promote Oncogenic Mutagenesis.
shared terms: protein, disorder

Weighed against this report's own most characteristic terms: rpl10, variant, mrxs35, gene, microcephaly, k78e, missense, allele, disease, loss, ul16, protein, zebrafish, subunit, disorder, epilepsy, xq28, functional, x-linked, disability.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	36
Resolved	34
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	14
Terms named correctly	5
Terms named as a different term	8
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001999 (1 mention) - the report calls it "Very frequent"; HP calls it Abnormal facial shape
HP:0001250 (1 mention) - the report calls it "Frequent"; HP calls it Seizure
HP:0000717 (1 mention) - the report calls it "Frequent"; HP calls it Autism
HP:0001561 (1 mention) - the report calls it "Frequent (3/4)"; HP calls it Polyhydramnios
HP:0004322 (1 mention) - the report calls it "Frequent"; HP calls it Short stature
HP:0000546 (1 mention) - the report calls it "Subset"; HP calls it Retinal degeneration
HP:0000365 (1 mention) - the report calls it "Subset"; HP calls it Hearing impairment
HP:0001627 (1 mention) - the report calls it "Subset"; HP calls it Abnormal heart morphology

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0022618 (1 mention) - the report calls it "ribonucleoprotein complex assembly"; GO calls it protein-RNA complex assembly, and lists "ribonucleoprotein complex assembly" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.

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Medical Actions

Diagnosis

Prevalence

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References & Deep Research

References

Deep Research

Key Findings

Finding 1 — MRXS35 is caused by hemizygous missense variants in RPL10 (uL16), an X-linked ribosomopathy

Finding 2 — RPL10 is highly intolerant to loss-of-function and missense variation

Finding 3 — Clinical spectrum: syndromic ID with epilepsy, ASD, microcephaly, dysmorphism, and congenital anomalies

Finding 4 — Mechanism: germline hypomorphic variants impair translation and increase apoptosis; distinct somatic R98S drives leukemia

Finding 5 — RPL10/uL16 protein: 214-aa cytoplasmic large-subunit ribosomal protein with resolved structures

Finding 6 — ClinVar landscape and cross-species orthologs

Finding 7 — Novel p.Arg116Gln allele expands genotype, phenotype, and functional evidence

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver