LSM7-related Leukodystrophy and Cerebellar Atrophy

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Inheritance

1

Autosomal recessive HP:0000007

Homozygous and compound heterozygous LSM7 missense genotypes, each allele inherited from a heterozygous unaffected parent.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:35047835 SUPPORT Human clinical

"Targeted Sanger sequencing confirmed the presence of the variant as homozygous in the affected individual, with both parents being carriers"

Homozygous affected child of two heterozygous carrier parents.

PMID:39420558 SUPPORT Human clinical

"Sanger sequencing consistently detected the variants in the parents, the affected case, but not in the unaffected sibling"

Compound heterozygous proband with one variant from each parent, consistent with recessive inheritance.

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Mechanistic Hypotheses

2

LSM2-8 / U6 snRNP splicing defect

lsm2_8_splicing_defect EMERGING

Evidence balance 1 support

Misassembly of the nuclear LSM2-8 ring impairs its chaperone role for U6 snRNA and its association with U4/U6.U5 tri-snRNP factors, compromising spliceosome function in vulnerable neural and glial cells. Reduced tri-snRNP factor binding is shown in HEK293 pull-downs; no splicing readout, U6 snRNA level or RNA-seq has been reported in patient cells.

Pathograph links

LSM1-7 and LSM2-8 Ring Misassembly -> Impaired U6 snRNP and Tri-snRNP Association DIRECT

Impaired U6 snRNP and Tri-snRNP Association -> Oligodendrocyte Apoptosis INDIRECT UNKNOWN INTERMEDIATES

Impaired U6 snRNP and Tri-snRNP Association -> Impaired Cerebellar Development INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:35047835 SUPPORT In vitro / ex vivo

"These splicing factors are required for the formation of the U4/U6/U5 tri-snRNP complex, an important precursor in the major spliceosome reaction."

The mutant LSM7 loses tri-snRNP interactors, which motivates a splicing model.

LSM1-7 / PATL1 mRNA decapping and decay defect

lsm1_7_mrna_decay_defect EMERGING

Evidence balance 1 support

Misassembly of the cytoplasmic LSM1-7 ring reduces its association with PATL1 and EDC4 and so impairs deadenylation-dependent decapping and 5'-3' mRNA decay, with downstream dysregulation of transcripts needed for oligodendrocyte and cerebellar development. Loss of the decay-factor interactions is shown in HEK293 pull-downs; no mRNA decay assay has been reported in patient cells.

Pathograph links

LSM1-7 and LSM2-8 Ring Misassembly -> Impaired LSM1-7 Mediated mRNA Decapping and Decay DIRECT

Impaired LSM1-7 Mediated mRNA Decapping and Decay -> Oligodendrocyte Apoptosis INDIRECT UNKNOWN INTERMEDIATES

Impaired LSM1-7 Mediated mRNA Decapping and Decay -> Impaired Cerebellar Development INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:35047835 SUPPORT In vitro / ex vivo

"the p.Asp41Asn and p.Arg69Pro mutants showed reduced interaction with the mRNA decay factors PATL1 and EDC4"

The mutant LSM7 loses the LSM1-7 decay partners, which motivates an mRNA decay model.

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Discussions and Knowledge Gaps

1

Is LSM7-related leukodystrophy driven by loss of LSM2-8 / U6 snRNP splicing function, loss of LSM1-7 mRNA decapping and decay, or both?

KNOWLEDGE GAP OPEN gap_lsm7_splicing_versus_mrna_decay

Attached to

pathophysiology#Impaired U6 snRNP and Tri-snRNP Association pathophysiology#Impaired LSM1-7 Mediated mRNA Decapping and Decay mechanistic_hypotheses#lsm2_8_splicing_defect mechanistic_hypotheses#lsm1_7_mrna_decay_defect

The only molecular readout is HEK293 pull-down showing both rings misassemble and lose both decay (PATL1, EDC4) and tri-snRNP partners. No study has measured U6 snRNA levels, splicing, or mRNA decay in patient cells or in oligodendrocytes, so neither arm can yet be preferred.

Proposed experiments

Splicing and mRNA decay profiling in LSM7 patient-derived glia

lsm7_patient_cell_rna_processing

Measure U6 snRNA abundance, transcriptome-wide splicing and mRNA half-lives in patient fibroblasts and iPSC-derived oligodendrocytes and neurons carrying biallelic LSM7 variants, against isogenic corrected controls.

Would support

pathophysiology#Impaired U6 snRNP and Tri-snRNP Association pathophysiology#Impaired LSM1-7 Mediated mRNA Decapping and Decay

Supporting outcome

Reduced U6 snRNA with intron retention or exon skipping supports the splicing arm.
Stabilized oligoadenylated mRNAs with delayed decapping support the decay arm.

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"Further investigation in patient-derived cells would be of high interest to better understand which aspects of RNA processing are mostly impaired and which genes are affected."

The authors state that which RNA processing arm is impaired is unknown.

PMID:35047835 SUPPORT In vitro / ex vivo

"The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies"

Neither arm is established as the disease mechanism.

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Pathophysiology

7

Biallelic LSM7 Missense Variants

Biallelic missense variants at Asp41 (an RNA-contacting Sm motif I residue) or Arg69 (an LSM5-contacting residue) reduce LSM7 abundance and its ability to bind its ring partners. LSM7 is a core subunit of LSM2-8, the U6 snRNP component of the spliceosome, which is the basis for conformance to the spliceosome module; LSM7 is equally a subunit of the non-spliceosomal LSM1-7 decay complex. Patient fibroblasts carrying homozygous p.Asp41Asn have reduced LSM7 mRNA and protein.

LSM7 hgnc:20470

RNA binding GO:0003723 ↓ DECREASED

Lsm2-8 complex GO:0120115 Lsm1-7-Pat1 complex GO:1990726

Downstream

LSM1-7 and LSM2-8 Ring Misassembly

Show evidence (3 references)

PMID:35047835 SUPPORT In vitro / ex vivo

"A decreased amount of LSM7 protein (p < 0.001) was seen in the affected individual as compared to control individuals"

Patient fibroblasts show reduced LSM7 protein.

PMID:35047835 SUPPORT INDIRECT Computational

"Since the p.Asp41Asn variant is located on a conserved RNA contacting residue in the Sm motif-I of LSM7"

Places Asp41 at an RNA-contacting residue by structural and conservation reasoning, grounding the RNA binding annotation indirectly.

PMID:39420558 SUPPORT BACKGROUND Other

"LSM 2–8 act as a chaperone protein complex in the nucleus for U6 small nuclear RNA (U6 snRNA), a spliceosome component and contributes to its nuclear retention."

Background establishing LSM2-8, which contains LSM7, as a U6 snRNP spliceosome component.

LSM1-7 and LSM2-8 Ring Misassembly

In HEK293 affinity purification-mass spectrometry, FLAG-tagged LSM7 p.Asp41Asn and p.Arg69Pro co-purify far less of the other LSM subunits of both rings than wild-type LSM7, and lose most known interactors of both complexes. This is the only molecular defect demonstrated so far; it does not distinguish which ring's loss is pathogenic.

LSM1-7 / PATL1 mRNA decapping and decay defect LSM2-8 / U6 snRNP splicing defect

Lsm2-8 complex GO:0120115 Lsm1-7-Pat1 complex GO:1990726

Downstream

Impaired U6 snRNP and Tri-snRNP Association

Impaired LSM1-7 Mediated mRNA Decapping and Decay

Show evidence (1 reference)

PMID:35047835 SUPPORT In vitro / ex vivo

"However, pull-downs from lysates of HEK293 cells producing the p.Asp41Asn or p.Arg69Pro variants revealed dramatically reduced association of the mutated LSM7 protein with the other LSM proteins constituting the LSM1-7 and LSM2-8 complexes."

Direct demonstration that both rings misassemble with the variant subunit.

Impaired U6 snRNP and Tri-snRNP Association

Variant LSM7 shows reduced interaction with the tri-snRNP factors PRPF3, PRPF4, SART3 and SNRNP200 in HEK293 pull-downs, consistent with a compromised U6 snRNP. No splicing change has been measured, so this node is not conformed to the spliceosome module's mis-splicing node.

LSM2-8 / U6 snRNP splicing defect

U6 snRNA binding GO:0017070 ↓ DECREASED

U6 snRNP GO:0005688 U4/U6 x U5 tri-snRNP complex GO:0046540

Downstream

Oligodendrocyte Apoptosis

Impaired Cerebellar Development

Show evidence (1 reference)

PMID:35047835 SUPPORT In vitro / ex vivo

"as well as with triple small nuclear ribonucleoprotein (tri-snRNP) factors including PRPF3, PRPF4, SART3, and SNRNP200"

Loss of tri-snRNP partners in the HEK293 interactome.

Impaired LSM1-7 Mediated mRNA Decapping and Decay

Variant LSM7 shows reduced interaction with the decapping activators PATL1 and EDC4 in HEK293 pull-downs. A decay defect is inferred from these lost interactions; mRNA half-life or decapping has not been measured.

LSM1-7 / PATL1 mRNA decapping and decay defect

deadenylation-dependent decapping of nuclear-transcribed mRNA GO:0000290 ↓ DECREASED

Downstream

Oligodendrocyte Apoptosis

Impaired Cerebellar Development

Show evidence (1 reference)

PMID:35047835 SUPPORT In vitro / ex vivo

"the p.Asp41Asn and p.Arg69Pro mutants showed reduced interaction with the mRNA decay factors PATL1 and EDC4"

Loss of the LSM1-7 decay partners in the HEK293 interactome.

Oligodendrocyte Apoptosis

In lsm7 CRISPR-Cas9 knockdown zebrafish, apoptosis of olig2-positive oligodendrocyte-lineage cells is increased and is rescued by wild-type but not p.Asp41Asn or p.Arg69Pro human LSM7. Evidence is from zebrafish only; oligodendrocyte loss has not been shown in patient tissue.

oligodendrocyte CL:0000128

oligodendrocyte apoptotic process GO:0097252 ↑ INCREASED

Animal models

lsm7 CRISPR-Cas9 crispant zebrafish Zebrafish recapitulates Increased oligodendrocyte-lineage apoptosis, rescued by wild-type but not variant human LSM7.

Downstream

Cerebral White Matter Disease

Show evidence (1 reference)

PMID:35047835 SUPPORT Model organism

"We found that apoptosis of oligodendrocytes was significantly increased in Lsm7-Crispants (p < 0.01) (Figures 5H and 5I) and could be rescued by concomitant injection of LSM7full-length cRNA but not by the LSM7Asp41Asn or LSM7Arg69Pro cRNAs"

Zebrafish oligodendrocyte apoptosis with allele-specific failure of rescue.

Cerebral White Matter Disease

Multifocal deep and periventricular T2/FLAIR white matter hyperintensity, progressive between 17 and 35 months in the first individual, read as a leukodystrophy. Whether this is hypomyelination or demyelination has not been established histologically.

Downstream

Leukodystrophy

Spastic tetraparesis

Global developmental delay

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"Brain MRI conducted at the age of 6 years showed bilateral, asymmetrical, and multifocal T2/FLAIR hyperintensities in the deep white matter involving the semioval centers and periventricular regions"

White matter signal abnormality in the second individual.

PMID:35047835 SUPPORT Human clinical

"His MRIs showed cerebellar hypoplasia and progressive white matter signal abnormalities between 17 and 35 months, indicative of a leukodystrophy"

Progressive white matter disease in the first individual.

Impaired Cerebellar Development

Reduced cerebellar vermis and enlarged interfolial spaces in both individuals, called hypoplasia at 17-35 months in one and atrophy at 6 years (after a normal MRI at 2 months) in the other. lsm7 knockdown zebrafish have a small cerebellum and brain.

Animal models

lsm7 CRISPR-Cas9 crispant zebrafish Zebrafish partially recapitulates Reduced brain and eye size and a small cerebellum, with reduced motor response to light.

Downstream

Cerebellar atrophy

Ataxia

Nystagmus

Global developmental delay

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"Importantly, both patients’ MRIs show a reduced size of the cerebellar vermis compared with an age-matched control and an enlargement of cerebellar interfolial spaces."

Shared cerebellar imaging finding in both individuals.

PMID:35047835 SUPPORT Model organism

"Interestingly, the hypoplastic cerebellum in individual 1 corresponded to the small cerebellar phenotype observed in Lsm7-Crispants."

The zebrafish knockdown reproduces a small cerebellum.

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Pathograph

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Phenotypes

13

Digestive 1

Feeding difficulties 1/2 HP:0011968

Show evidence (1 reference)

PMID:35047835 SUPPORT Human clinical

"He presented with spastic quadriparesis, white matter anomalies, developmental delay, progressive sensorineural hearing loss, hypospadias, and feeding difficulties."

Feeding difficulties in the first individual.

Ear 1

Sensorineural hearing impairment 1/2 HP:0000407

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Individual 1 presented with hypospadias and progressive sensorineural hearing loss which was not found in our case."

Present in one of the two individuals.

Eye 3

Nystagmus 1/1 HP:0000639

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia"

Nystagmus in the second individual.

Oculomotor apraxia 1/1 HP:0000657

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia"

Oculomotor apraxia in the second individual.

Strabismus 1/2 HP:0000486

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Additional clinical findings include a right eye strabismus."

Strabismus in the second individual.

Genitourinary 1

Hypospadias 1/2 HP:0000047

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Individual 1 presented with hypospadias and progressive sensorineural hearing loss which was not found in our case."

Present in one of the two individuals.

Musculoskeletal 2

Spastic tetraparesis 2/2 HP:0001285

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Indeed, they both have spastic quadriparesis forcing them to use a wheelchair to move around, associated with a global developmental delay."

Spastic quadriparesis in both individuals.

Axial hypotonia 1/2 HP:0008936

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Neurological features found during his clinical examination included axial hypotonia, postural instability"

Axial hypotonia in the second individual.

Nervous System 5

Leukodystrophy 2/2 HP:0002415

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"Furthermore, they exhibited similar white substance abnormalities indicative of a leukodystrophy."

Both individuals have leukodystrophy-pattern white matter disease.

Cerebellar atrophy 2/2 HP:0001272

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"It also displayed cerebellar atrophy (Figure 1) in the context of a normal MRI at 2 months"

Postnatally acquired cerebellar atrophy in the second individual.

PMID:39420558 SUPPORT Human clinical

"However, in the context of the developing cerebellum, atrophy and hypoplasia are often not distinguishable."

Justifies treating the first individual's hypoplasia as the same finding.

Global developmental delay 2/2 HP:0001263

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"He is able to walk a few steps with a walking frame assistance, speaks only five words, points with his finger to ask for things, and responds to simple requests."

Severity of the delay in the second individual.

PMID:35047835 SUPPORT Human clinical

"He presented with spastic quadriparesis, white matter anomalies, developmental delay, progressive sensorineural hearing loss, hypospadias, and feeding difficulties."

Developmental delay in the first individual.

Ataxia 1/1 HP:0001251

Show evidence (2 references)

PMID:39420558 SUPPORT Human clinical

"Neurological features found during his clinical examination included axial hypotonia, postural instability, spasticity of the four limbs, extrapyramidal dyskinesia, and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia."

Ataxia among the cerebellar signs.

PMID:39420558 SUPPORT Human clinical

"The first signs of cerebellar dysfunction were observed at 4 years old."

Onset of cerebellar signs.

Extrapyramidal dyskinesia 1/1 HP:0007308

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"postural instability, spasticity of the four limbs, extrapyramidal dyskinesia"

Extrapyramidal dyskinesia in the second individual.

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Genetic Associations

1

LSM7 (Causative biallelic missense variants)

Gene: LSM7 hgnc:20470 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:39420558 SUPPORT Human clinical

"we confirm that LSM7 disruption causes a neurodevelopmental disorder characterized by leukodystrophy and cerebellar atrophy"

The second independent family confirms LSM7 as the disease gene.

Variants (3)

p.Asp41Asn Pathogenic

LSM7 c.121G>A (NM_016199.2), found homozygous in the first reported individual and in trans with p.Arg69Trp in the second. Asp41 is a conserved RNA-contacting residue in Sm motif I.

Show evidence (1 reference)

PMID:35047835 SUPPORT Human clinical

"These analyses revealed a homozygous variant in LSM7 (GenBank: NM_016199.2; GRCh37/hg19) at position c.121G>A (p.Asp41Asn)"

Identifies the homozygous variant in the first affected individual.

p.Arg69Trp

LSM7 c.205C>T, maternally inherited in the second reported individual. Arg69 makes polar contacts with LSM5 in both rings; tryptophan removes them in structural modelling. Not functionally tested.

Show evidence (1 reference)

PMID:39420558 SUPPORT Computational

"The amino acid Arg69 of LSM7 establishes polar contacts with LSM5, at the level of Glu35 (Figure 2D) as detected in yeast, in both Lsm1-7 and Lsm2-8 complexes."

Structural modelling places Arg69 at the LSM5 interface of both rings.

p.Arg69Pro

LSM7 c.206G>C, carried heterozygously by both parents of a family with recurrent fetal deaths; no fetus was genotyped, so its homozygous effect is presumed. Impairs ring assembly in HEK293 cells.

Show evidence (1 reference)

PMID:35047835 SUPPORT Human clinical

"The multiple fetal deaths are thereby presumed to be caused by the homozygous variant in LSM7."

The fetal genotype is presumed rather than observed.

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Animal Models

1

lsm7 CRISPR-Cas9 crispant zebrafish

F0 zebrafish injected with lsm7 exon 3 sgRNA and Cas9 protein, with rescue by wild-type or variant human LSM7 cRNA.

Species

Zebrafish

Genotype

lsm7 exon 3 sgRNA plus Cas9 F0 crispant

Publication

PMID:35047835

Pathograph links

Oligodendrocyte Apoptosis recapitulates fidelity: moderate observes: cellular Increased oligodendrocyte-lineage apoptosis, rescued by wild-type but not variant human LSM7.

Limitations: Mosaic F0 knockdown rather than a germline missense model; olig2:dsRed also labels precursors and motor neurons; myelin itself and LSM ring assembly or splicing were not measured in the fish.

Show evidence (1 reference)

PMID:35047835 SUPPORT Model organism

"We found that apoptosis of oligodendrocytes was significantly increased in Lsm7-Crispants (p < 0.01) (Figures 5H and 5I) and could be rescued by concomitant injection of LSM7full-length cRNA but not by the LSM7Asp41Asn or LSM7Arg69Pro cRNAs"

Supports the crispant as informative for the oligodendrocyte node.

Impaired Cerebellar Development partially recapitulates fidelity: low observes: tissue Reduced brain and eye size and a small cerebellum, with reduced motor response to light.

Limitations: Reduction in overall brain size is not specific to the cerebellum, and the zebrafish phenotype is embryonic rather than the postnatal-onset atrophy seen in one patient.

Show evidence (2 references)

PMID:35047835 SUPPORT Model organism

"a mild phenotype who displayed normal trunk morphology but brain and eye size reduction"

Brain size reduction in the crispants.

+ 1 more reference

{ }

Source YAML

click to show

name: LSM7-related Leukodystrophy and Cerebellar Atrophy
creation_date: "2026-10-28T06:00:00Z"
category: Mendelian
description: >-
  An ultra-rare autosomal recessive neurodevelopmental disorder caused by
  biallelic missense variants in LSM7, which encodes a subunit shared by the
  cytoplasmic LSM1-7 ring (mRNA decapping and decay) and the nuclear LSM2-8
  ring (U6 snRNA chaperone of the spliceosome). Two living, unrelated affected
  males have been reported, one homozygous for p.Asp41Asn and one compound
  heterozygous for p.Asp41Asn and p.Arg69Trp. Both have global developmental
  delay, spastic quadriparesis and MRI white matter signal abnormality
  indicative of a leukodystrophy together with cerebellar hypoplasia or
  atrophy; one also has progressive sensorineural hearing loss and hypospadias,
  the other ataxia, nystagmus, oculomotor apraxia and extrapyramidal
  dyskinesia. A consanguineous couple who were both heterozygous for
  p.Arg69Pro had recurrent fetal deaths, but no fetus was genotyped. The
  variants impair assembly of both LSM rings in human cells, and lsm7 loss in
  zebrafish increases oligodendrocyte apoptosis; whether the disease is driven
  by the splicing (LSM2-8) or the mRNA decay (LSM1-7) arm has not been tested.
disease_term:
  preferred_term: LSM7-related leukodystrophy and cerebellar atrophy
  term:
    id: MONDO:0978294
    label: LSM7-related leukodystrophy and cerebellar atrophy
synonyms: []
parents:
- Leukodystrophy
- Hereditary neurological disease
notes: >-
  Evidence base is two clinically characterized individuals (PMID:35047835 and
  PMID:39420558). The p.Arg69Pro fetal deaths are attributed to LSM7 only by
  parental carrier status, so the fetal findings (nuchal translucency,
  encephalocele, death at 32 weeks) are recorded here and not as phenotypes.
  No ClinGen gene-disease validity record exists for LSM7 in the committed
  ClinGen export, and no GeneReviews chapter covers the disorder.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous and compound heterozygous LSM7 missense genotypes, each allele
    inherited from a heterozygous unaffected parent.
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted Sanger sequencing confirmed the presence of the variant as homozygous in the affected individual, with both parents being carriers"
    explanation: Homozygous affected child of two heterozygous carrier parents.
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing consistently detected the variants in the parents, the affected case, but not in the unaffected sibling"
    explanation: Compound heterozygous proband with one variant from each parent, consistent with recessive inheritance.
genetic:
- name: LSM7
  gene_term:
    preferred_term: LSM7
    term:
      id: hgnc:20470
      label: LSM7
  association: Causative biallelic missense variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    No ClinGen gene-disease validity assertion exists for LSM7, so
    gene_disease_validity is left absent. Only two genotyped affected
    individuals are published.
  variants:
  - name: p.Asp41Asn
    description: >-
      LSM7 c.121G>A (NM_016199.2), found homozygous in the first reported
      individual and in trans with p.Arg69Trp in the second. Asp41 is a
      conserved RNA-contacting residue in Sm motif I.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:35047835
      reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These analyses revealed a homozygous variant in LSM7 (GenBank: NM_016199.2; GRCh37/hg19) at position c.121G>A (p.Asp41Asn)"
      explanation: Identifies the homozygous variant in the first affected individual.
  - name: p.Arg69Trp
    description: >-
      LSM7 c.205C>T, maternally inherited in the second reported individual.
      Arg69 makes polar contacts with LSM5 in both rings; tryptophan removes
      them in structural modelling. Not functionally tested.
    evidence:
    - reference: PMID:39420558
      reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The amino acid Arg69 of LSM7 establishes polar contacts with LSM5, at the level of Glu35 (Figure 2D) as detected in yeast, in both Lsm1-7 and Lsm2-8 complexes."
      explanation: Structural modelling places Arg69 at the LSM5 interface of both rings.
  - name: p.Arg69Pro
    description: >-
      LSM7 c.206G>C, carried heterozygously by both parents of a family with
      recurrent fetal deaths; no fetus was genotyped, so its homozygous effect
      is presumed. Impairs ring assembly in HEK293 cells.
    evidence:
    - reference: PMID:35047835
      reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The multiple fetal deaths are thereby presumed to be caused by the homozygous variant in LSM7."
      explanation: The fetal genotype is presumed rather than observed.
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we confirm that LSM7 disruption causes a neurodevelopmental disorder characterized by leukodystrophy and cerebellar atrophy"
    explanation: The second independent family confirms LSM7 as the disease gene.
mechanistic_hypotheses:
- hypothesis_group_id: lsm2_8_splicing_defect
  hypothesis_label: LSM2-8 / U6 snRNP splicing defect
  status: EMERGING
  description: >-
    Misassembly of the nuclear LSM2-8 ring impairs its chaperone role for U6
    snRNA and its association with U4/U6.U5 tri-snRNP factors, compromising
    spliceosome function in vulnerable neural and glial cells. Reduced
    tri-snRNP factor binding is shown in HEK293 pull-downs; no splicing
    readout, U6 snRNA level or RNA-seq has been reported in patient cells.
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These splicing factors are required for the formation of the U4/U6/U5 tri-snRNP complex, an important precursor in the major spliceosome reaction."
    explanation: The mutant LSM7 loses tri-snRNP interactors, which motivates a splicing model.
- hypothesis_group_id: lsm1_7_mrna_decay_defect
  hypothesis_label: LSM1-7 / PATL1 mRNA decapping and decay defect
  status: EMERGING
  description: >-
    Misassembly of the cytoplasmic LSM1-7 ring reduces its association with
    PATL1 and EDC4 and so impairs deadenylation-dependent decapping and 5'-3'
    mRNA decay, with downstream dysregulation of transcripts needed for
    oligodendrocyte and cerebellar development. Loss of the decay-factor
    interactions is shown in HEK293 pull-downs; no mRNA decay assay has been
    reported in patient cells.
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the p.Asp41Asn and p.Arg69Pro mutants showed reduced interaction with the mRNA decay factors PATL1 and EDC4"
    explanation: The mutant LSM7 loses the LSM1-7 decay partners, which motivates an mRNA decay model.
pathophysiology:
- name: Biallelic LSM7 Missense Variants
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic missense variants at Asp41 (an RNA-contacting Sm motif I
    residue) or Arg69 (an LSM5-contacting residue) reduce LSM7 abundance and
    its ability to bind its ring partners. LSM7 is a core subunit of LSM2-8,
    the U6 snRNP component of the spliceosome, which is the basis for
    conformance to the spliceosome module; LSM7 is equally a subunit of the
    non-spliceosomal LSM1-7 decay complex. Patient fibroblasts carrying
    homozygous p.Asp41Asn have reduced LSM7 mRNA and protein.
  genes:
  - preferred_term: LSM7
    term:
      id: hgnc:20470
      label: LSM7
  molecular_functions:
  - preferred_term: RNA binding
    term:
      id: GO:0003723
      label: RNA binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: Lsm2-8 complex
    term:
      id: GO:0120115
      label: Lsm2-8 complex
  - preferred_term: Lsm1-7-Pat1 complex
    term:
      id: GO:1990726
      label: Lsm1-7-Pat1 complex
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A decreased amount of LSM7 protein (p < 0.001) was seen in the affected individual as compared to control individuals"
    explanation: Patient fibroblasts show reduced LSM7 protein.
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Since the p.Asp41Asn variant is located on a conserved RNA contacting residue in the Sm motif-I of LSM7"
    explanation: Places Asp41 at an RNA-contacting residue by structural and conservation reasoning, grounding the RNA binding annotation indirectly.
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "LSM 2–8 act as a chaperone protein complex in the nucleus for U6 small nuclear RNA (U6 snRNA), a spliceosome component and contributes to its nuclear retention."
    explanation: Background establishing LSM2-8, which contains LSM7, as a U6 snRNP spliceosome component.
  downstream:
  - target: LSM1-7 and LSM2-8 Ring Misassembly
    causal_link_type: DIRECT
- name: LSM1-7 and LSM2-8 Ring Misassembly
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    In HEK293 affinity purification-mass spectrometry, FLAG-tagged LSM7
    p.Asp41Asn and p.Arg69Pro co-purify far less of the other LSM subunits of
    both rings than wild-type LSM7, and lose most known interactors of both
    complexes. This is the only molecular defect demonstrated so far; it does
    not distinguish which ring's loss is pathogenic.
  cellular_components:
  - preferred_term: Lsm2-8 complex
    term:
      id: GO:0120115
      label: Lsm2-8 complex
  - preferred_term: Lsm1-7-Pat1 complex
    term:
      id: GO:1990726
      label: Lsm1-7-Pat1 complex
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, pull-downs from lysates of HEK293 cells producing the p.Asp41Asn or p.Arg69Pro variants revealed dramatically reduced association of the mutated LSM7 protein with the other LSM proteins constituting the LSM1-7 and LSM2-8 complexes."
    explanation: Direct demonstration that both rings misassemble with the variant subunit.
  downstream:
  - target: Impaired U6 snRNP and Tri-snRNP Association
    causal_link_type: DIRECT
    hypothesis_groups:
    - lsm2_8_splicing_defect
  - target: Impaired LSM1-7 Mediated mRNA Decapping and Decay
    causal_link_type: DIRECT
    hypothesis_groups:
    - lsm1_7_mrna_decay_defect
- name: Impaired U6 snRNP and Tri-snRNP Association
  role: hypothesized_effector
  biological_scale: MOLECULAR
  description: >-
    Variant LSM7 shows reduced interaction with the tri-snRNP factors PRPF3,
    PRPF4, SART3 and SNRNP200 in HEK293 pull-downs, consistent with a
    compromised U6 snRNP. No splicing change has been measured, so this node
    is not conformed to the spliceosome module's mis-splicing node.
  cellular_components:
  - preferred_term: U6 snRNP
    term:
      id: GO:0005688
      label: U6 snRNP
  - preferred_term: U4/U6 x U5 tri-snRNP complex
    term:
      id: GO:0046540
      label: U4/U6 x U5 tri-snRNP complex
  molecular_functions:
  - preferred_term: U6 snRNA binding
    term:
      id: GO:0017070
      label: U6 snRNA binding
    modifier: DECREASED
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "as well as with triple small nuclear ribonucleoprotein (tri-snRNP) factors including PRPF3, PRPF4, SART3, and SNRNP200"
    explanation: Loss of tri-snRNP partners in the HEK293 interactome.
  downstream:
  - target: Oligodendrocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lsm2_8_splicing_defect
  - target: Impaired Cerebellar Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lsm2_8_splicing_defect
- name: Impaired LSM1-7 Mediated mRNA Decapping and Decay
  role: hypothesized_effector
  biological_scale: MOLECULAR
  description: >-
    Variant LSM7 shows reduced interaction with the decapping activators PATL1
    and EDC4 in HEK293 pull-downs. A decay defect is inferred from these lost
    interactions; mRNA half-life or decapping has not been measured.
  biological_processes:
  - preferred_term: deadenylation-dependent decapping of nuclear-transcribed mRNA
    term:
      id: GO:0000290
      label: deadenylation-dependent decapping of nuclear-transcribed mRNA
    modifier: DECREASED
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the p.Asp41Asn and p.Arg69Pro mutants showed reduced interaction with the mRNA decay factors PATL1 and EDC4"
    explanation: Loss of the LSM1-7 decay partners in the HEK293 interactome.
  downstream:
  - target: Oligodendrocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lsm1_7_mrna_decay_defect
  - target: Impaired Cerebellar Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lsm1_7_mrna_decay_defect
- name: Oligodendrocyte Apoptosis
  conforms_to: "cns_myelin_failure#Oligodendrocyte Differentiation Arrest and Death"
  role: cellular_consequence
  biological_scale: CELLULAR
  description: >-
    In lsm7 CRISPR-Cas9 knockdown zebrafish, apoptosis of olig2-positive
    oligodendrocyte-lineage cells is increased and is rescued by wild-type but
    not p.Asp41Asn or p.Arg69Pro human LSM7. Evidence is from zebrafish only;
    oligodendrocyte loss has not been shown in patient tissue.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: oligodendrocyte apoptotic process
    term:
      id: GO:0097252
      label: oligodendrocyte apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that apoptosis of oligodendrocytes was significantly increased in Lsm7-Crispants (p < 0.01) (Figures 5H and 5I) and could be rescued by concomitant injection of LSM7full-length cRNA but not by the LSM7Asp41Asn or LSM7Arg69Pro cRNAs"
    explanation: Zebrafish oligodendrocyte apoptosis with allele-specific failure of rescue.
  downstream:
  - target: Cerebral White Matter Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cerebral White Matter Disease
  role: tissue_consequence
  biological_scale: TISSUE
  description: >-
    Multifocal deep and periventricular T2/FLAIR white matter hyperintensity,
    progressive between 17 and 35 months in the first individual, read as a
    leukodystrophy. Whether this is hypomyelination or demyelination has not
    been established histologically.
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI conducted at the age of 6 years showed bilateral, asymmetrical, and multifocal T2/FLAIR hyperintensities in the deep white matter involving the semioval centers and periventricular regions"
    explanation: White matter signal abnormality in the second individual.
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His MRIs showed cerebellar hypoplasia and progressive white matter signal abnormalities between 17 and 35 months, indicative of a leukodystrophy"
    explanation: Progressive white matter disease in the first individual.
  downstream:
  - target: Leukodystrophy
    causal_link_type: DIRECT
  - target: Spastic tetraparesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Cerebellar Development
  role: tissue_consequence
  biological_scale: TISSUE
  description: >-
    Reduced cerebellar vermis and enlarged interfolial spaces in both
    individuals, called hypoplasia at 17-35 months in one and atrophy at 6
    years (after a normal MRI at 2 months) in the other. lsm7 knockdown
    zebrafish have a small cerebellum and brain.
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, both patients’ MRIs show a reduced size of the cerebellar vermis compared with an age-matched control and an enlargement of cerebellar interfolial spaces."
    explanation: Shared cerebellar imaging finding in both individuals.
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, the hypoplastic cerebellum in individual 1 corresponded to the small cerebellar phenotype observed in Lsm7-Crispants."
    explanation: The zebrafish knockdown reproduces a small cerebellum.
  downstream:
  - target: Cerebellar atrophy
    causal_link_type: DIRECT
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Leukodystrophy
  category: Neurological
  frequency: "2/2"
  description: >-
    White matter signal abnormality on MRI indicative of a leukodystrophy in
    both reported individuals, progressive in the first.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, they exhibited similar white substance abnormalities indicative of a leukodystrophy."
    explanation: Both individuals have leukodystrophy-pattern white matter disease.
- name: Cerebellar atrophy
  category: Neurological
  frequency: "2/2"
  description: >-
    Cerebellar vermian and hemispheric atrophy at 6 years in the second
    individual; cerebellar hypoplasia at 17-35 months in the first, which the
    authors note is often indistinguishable from atrophy in the developing
    cerebellum.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It also displayed cerebellar atrophy (Figure 1) in the context of a normal MRI at 2 months"
    explanation: Postnatally acquired cerebellar atrophy in the second individual.
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in the context of the developing cerebellum, atrophy and hypoplasia are often not distinguishable."
    explanation: Justifies treating the first individual's hypoplasia as the same finding.
- name: Spastic tetraparesis
  category: Neurological
  frequency: "2/2"
  description: Spastic quadriparesis leaving both individuals wheelchair dependent.
  phenotype_term:
    preferred_term: Spastic quadriparesis
    term:
      id: HP:0001285
      label: Spastic tetraparesis
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, they both have spastic quadriparesis forcing them to use a wheelchair to move around, associated with a global developmental delay."
    explanation: Spastic quadriparesis in both individuals.
- name: Global developmental delay
  category: Neurological
  frequency: "2/2"
  description: >-
    Global developmental delay in both individuals; at 6 years the second
    walks a few steps with a frame and speaks five words, without regression.
    Both are recorded as having intellectual disability in the 2024 clinical
    table.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He is able to walk a few steps with a walking frame assistance, speaks only five words, points with his finger to ask for things, and responds to simple requests."
    explanation: Severity of the delay in the second individual.
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented with spastic quadriparesis, white matter anomalies, developmental delay, progressive sensorineural hearing loss, hypospadias, and feeding difficulties."
    explanation: Developmental delay in the first individual.
- name: Ataxia
  category: Neurological
  frequency: "1/1"
  description: >-
    Cerebellar ataxia with limb tremor, first noted at 4 years, in the second
    individual; not assessed in the first.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features found during his clinical examination included axial hypotonia, postural instability, spasticity of the four limbs, extrapyramidal dyskinesia, and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia."
    explanation: Ataxia among the cerebellar signs.
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first signs of cerebellar dysfunction were observed at 4 years old."
    explanation: Onset of cerebellar signs.
- name: Nystagmus
  category: Neurological
  frequency: "1/1"
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia"
    explanation: Nystagmus in the second individual.
- name: Oculomotor apraxia
  category: Neurological
  frequency: "1/1"
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and cerebellar features such as nystagmus, oculomotor apraxia, tremors of the limbs, and ataxia"
    explanation: Oculomotor apraxia in the second individual.
- name: Extrapyramidal dyskinesia
  category: Neurological
  frequency: "1/1"
  phenotype_term:
    preferred_term: Extrapyramidal dyskinesia
    term:
      id: HP:0007308
      label: Extrapyramidal dyskinesia
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postural instability, spasticity of the four limbs, extrapyramidal dyskinesia"
    explanation: Extrapyramidal dyskinesia in the second individual.
- name: Axial hypotonia
  category: Neurological
  frequency: "1/2"
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features found during his clinical examination included axial hypotonia, postural instability"
    explanation: Axial hypotonia in the second individual.
- name: Sensorineural hearing impairment
  category: Neurological
  frequency: "1/2"
  description: Progressive sensorineural hearing loss in the first individual, absent in the second.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 1 presented with hypospadias and progressive sensorineural hearing loss which was not found in our case."
    explanation: Present in one of the two individuals.
- name: Hypospadias
  category: Genitourinary
  frequency: "1/2"
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 1 presented with hypospadias and progressive sensorineural hearing loss which was not found in our case."
    explanation: Present in one of the two individuals.
- name: Feeding difficulties
  category: Gastrointestinal
  frequency: "1/2"
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented with spastic quadriparesis, white matter anomalies, developmental delay, progressive sensorineural hearing loss, hypospadias, and feeding difficulties."
    explanation: Feeding difficulties in the first individual.
- name: Strabismus
  category: Ophthalmological
  frequency: "1/2"
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical findings include a right eye strabismus."
    explanation: Strabismus in the second individual.
animal_models:
- name: lsm7 CRISPR-Cas9 crispant zebrafish
  species: Zebrafish
  genotype: lsm7 exon 3 sgRNA plus Cas9 F0 crispant
  publication: PMID:35047835
  description: >-
    F0 zebrafish injected with lsm7 exon 3 sgRNA and Cas9 protein, with rescue
    by wild-type or variant human LSM7 cRNA.
  modeled_mechanisms:
  - target: Oligodendrocyte Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Increased oligodendrocyte-lineage apoptosis, rescued by wild-type but not variant human LSM7.
    limitations: >-
      Mosaic F0 knockdown rather than a germline missense model; olig2:dsRed
      also labels precursors and motor neurons; myelin itself and LSM ring
      assembly or splicing were not measured in the fish.
    evidence:
    - reference: PMID:35047835
      reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that apoptosis of oligodendrocytes was significantly increased in Lsm7-Crispants (p < 0.01) (Figures 5H and 5I) and could be rescued by concomitant injection of LSM7full-length cRNA but not by the LSM7Asp41Asn or LSM7Arg69Pro cRNAs"
      explanation: Supports the crispant as informative for the oligodendrocyte node.
  - target: Impaired Cerebellar Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Reduced brain and eye size and a small cerebellum, with reduced motor response to light.
    limitations: >-
      Reduction in overall brain size is not specific to the cerebellum, and
      the zebrafish phenotype is embryonic rather than the postnatal-onset
      atrophy seen in one patient.
    evidence:
    - reference: PMID:35047835
      reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "a mild phenotype who displayed normal trunk morphology but brain and eye size reduction"
      explanation: Brain size reduction in the crispants.
    - reference: PMID:35047835
      reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that larvae response to light stimuli was significantly reduced in the Lsm7-Crispants (p < 0.001)"
      explanation: Motor behavior deficit in the crispants.
discussions:
- discussion_id: gap_lsm7_splicing_versus_mrna_decay
  prompt: >-
    Is LSM7-related leukodystrophy driven by loss of LSM2-8 / U6 snRNP
    splicing function, loss of LSM1-7 mRNA decapping and decay, or both?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired U6 snRNP and Tri-snRNP Association
  - pathophysiology#Impaired LSM1-7 Mediated mRNA Decapping and Decay
  - mechanistic_hypotheses#lsm2_8_splicing_defect
  - mechanistic_hypotheses#lsm1_7_mrna_decay_defect
  rationale: >-
    The only molecular readout is HEK293 pull-down showing both rings
    misassemble and lose both decay (PATL1, EDC4) and tri-snRNP partners. No
    study has measured U6 snRNA levels, splicing, or mRNA decay in patient
    cells or in oligodendrocytes, so neither arm can yet be preferred.
  evidence:
  - reference: PMID:39420558
    reference_title: "LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further investigation in patient-derived cells would be of high interest to better understand which aspects of RNA processing are mostly impaired and which genes are affected."
    explanation: The authors state that which RNA processing arm is impaired is unknown.
  - reference: PMID:35047835
    reference_title: "Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies"
    explanation: Neither arm is established as the disease mechanism.
  proposed_experiments:
  - experiment_id: lsm7_patient_cell_rna_processing
    name: Splicing and mRNA decay profiling in LSM7 patient-derived glia
    description: >-
      Measure U6 snRNA abundance, transcriptome-wide splicing and mRNA
      half-lives in patient fibroblasts and iPSC-derived oligodendrocytes
      and neurons carrying biallelic LSM7 variants, against isogenic
      corrected controls.
    would_support:
    - pathophysiology#Impaired U6 snRNP and Tri-snRNP Association
    - pathophysiology#Impaired LSM1-7 Mediated mRNA Decapping and Decay
    supporting_outcome:
    - >-
      Reduced U6 snRNA with intron retention or exon skipping supports the
      splicing arm.
    - >-
      Stabilized oligoadenylated mRNAs with delayed decapping support the
      decay arm.

LSM7-related Leukodystrophy and Cerebellar Atrophy

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