👪

Inheritance

1

Autosomal Recessive HP:0000007

All confirmed cases with SLC35D1 mutations have been homozygous or compound heterozygous for loss-of-function alleles. Multiple reports describe consanguineous parents, consistent with autosomal recessive inheritance. The original description documented autosomal recessive inheritance in affected families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"a distinct neonatal lethal chondrodysplasia inherited as an autosomal recessive trait"

Original description establishes autosomal recessive inheritance pattern.

PMID:19508970 SUPPORT Human Clinical

"Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias"

Confirms autosomal recessive inheritance and nosology classification.

◆

Subtypes

2

Classic Lethal

The classic perinatally lethal form caused by complete loss-of-function SLC35D1 mutations. Presents with all cardinal features and results in death in utero or shortly after birth.

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"a distinct neonatal lethal chondrodysplasia inherited as an autosomal recessive trait"

Original description of the classic lethal form with characteristic radiographic and histologic features.

PMID:17952091 SUPPORT Human Clinical

"loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia"

Identifies complete loss-of-function SLC35D1 mutations as the cause of the classic lethal form.

Mild Nonlethal (Hypomorphic SLC35D1)

A milder form caused by hypomorphic missense SLC35D1 mutations that reduce but do not abolish transporter activity. Patients survive with short stature, mild mesomelia, genu valgum, and narrow thorax.

Show evidence (2 references)

PMID:35934917 SUPPORT Human Clinical

"The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax"

Describes the mild nonlethal phenotype in a large family with a hypomorphic SLC35D1 variant.

PMID:38058750 SUPPORT Human Clinical

"Our observation confirms the existence of nonlethal skeletal dysplasias associated with biallelic SLC35D1 variants and suggests the existence of a phenotypic spectrum"

Independent confirmation of a phenotypic spectrum from lethal to mild skeletal dysplasia.

⚙

Pathophysiology

6

Defective Nucleotide-Sugar Transport

SLC35D1 encodes an endoplasmic reticulum nucleotide-sugar transporter that transports UDP-glucuronic acid and UDP-N-acetylgalactosamine from the cytoplasm into the ER lumen. These substrates are required for chondroitin sulfate biosynthesis. Loss-of-function mutations abolish transporter activity, leading to defective chondroitin sulfate chain synthesis on cartilage proteoglycan core proteins. The resulting proteoglycans have short, sparse chondroitin sulfate chains that cannot maintain normal cartilage extracellular matrix integrity.

Chondrocyte link Growth Plate Chondrocyte link

Nucleotide-Sugar Transmembrane Transport link Chondroitin Sulfate Proteoglycan Biosynthesis link

Downstream

Deficient Chondroitin Sulfate Proteoglycan Matrix Loss of SLC35D1 nucleotide-sugar transport limits ER-luminal substrates for chondroitin sulfate synthesis, producing shortened and sparse chondroitin sulfate chains on cartilage proteoglycans.

Show evidence (3 references)

PMID:17952091 SUPPORT Model Organism

"Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"

Slc35d1 knockout mice recapitulate the lethal skeletal dysplasia phenotype, confirming the gene's role in skeletal development.

PMID:17952091 SUPPORT Model Organism

"These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"

Demonstrates that SLC35D1 deficiency directly impairs chondroitin sulfate chain formation.

PMID:19508970 SUPPORT In Vitro

"Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars"

Functional assay demonstrates that the disease-causing missense mutation abolishes nucleotide-sugar transport activity.

Deficient Chondroitin Sulfate Proteoglycan Matrix

Defective chondroitin sulfate biosynthesis reduces both the length and number of chondroitin sulfate chains on cartilage proteoglycans. The resulting extracellular matrix contains reduced proteoglycan aggregates and cannot support normal growth plate organization, chondrocyte column formation, or endochondral skeletal morphogenesis.

Growth Plate Chondrocyte link

extracellular matrix organization link cartilage development involved in endochondral bone morphogenesis link

Downstream

Growth Plate Disorganization Reduced proteoglycan aggregate formation disrupts cartilage matrix integrity, producing the disorganized proliferating zone and abnormal chondrocyte morphology seen in the growth plate.

Show evidence (2 references)

PMID:17952091 SUPPORT Model Organism

"These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"

The mouse model demonstrates deficient chondroitin sulfate chain synthesis as the primary matrix defect.

PMID:19508970 SUPPORT Human Clinical

"Histological findings in SBD include large, round, and centrally located chondrocyte nuclei, scarce extracellular matrix, and an absence of columnar alignment of proliferating chondrocytes in the growth plate."

Human histopathology supports scarce cartilage extracellular matrix with disrupted chondrocyte columns.

Growth Plate Disorganization

Loss of functional chondroitin sulfate proteoglycans in the cartilage matrix disrupts the normal architecture of the epiphyseal growth plate. The proliferating zone is decreased, columnar alignment of chondrocytes is absent, and the extracellular matrix is scarce. Chondrocytes are round with centrally located nuclei and lack normal lacunar spaces. The cartilage is hypercellular and hypervascular. These changes severely impair endochondral ossification, resulting in the characteristic skeletal anomalies.

Growth Plate Chondrocyte link

Cartilage Development in Endochondral Bone Formation link Chondrocyte Differentiation link

Downstream

Vertebral and Pelvic Ossification Failure Disorganized growth plate cartilage impairs vertebral and pelvic ossification, producing platyspondyly and the characteristic hypoplastic snail-like ilia.

Appendicular Skeletal Shortening and Metaphyseal Expansion Abnormal cartilage matrix and chondrocyte organization impair limb growth, causing micromelia, dumbbell-shaped long bones, and milder surviving limb phenotypes when transporter activity is partially retained.

Thoracic Restriction and Pulmonary Hypoplasia Endochondral skeletal dysplasia affects ribs and the thoracic cage, producing a narrow bell-shaped thorax that can secondarily impair fetal lung expansion and cause pulmonary hypoplasia.

Short Ribs Rib growth plate disorganization produces short ribs as part of the lethal skeletal dysplasia pattern.

Show evidence (3 references)

PMID:17952091 SUPPORT Model Organism

"Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"

Mouse model demonstrates growth plate disorganization with decreased proliferation, round chondrocytes, and depleted matrix.

PMID:3799723 SUPPORT Human Clinical

"Chondro-osseous histology is characteristic with hypervascularity, increased cellular density, and normal size chondrocytes with a centrally located round nucleus and absence of lacunar space"

Original human histopathology description confirms characteristic growth plate findings.

PMID:11200994 SUPPORT Human Clinical

"The histology showed hypercellular and hypervascular cartilage with chondrocytes with centrally located nucleus"

Additional human case confirms the characteristic cartilage histology with hypercellularity and hypervascularization.

Vertebral and Pelvic Ossification Failure

Severe growth plate disorganization and defective endochondral ossification produce axial and pelvic skeletal abnormalities: flattened vertebral bodies, delayed posterior vertebral ossification, hypoplastic ilia with a medial snail-like projection, and abnormal timing of tarsal ossification.

Growth Plate Chondrocyte link

bone development link cartilage development involved in endochondral bone morphogenesis link

Downstream

Severe Platyspondyly Failed vertebral body ossification manifests as severe platyspondyly.

Hypoplastic Ilia with Snail-Like Configuration Defective pelvic cartilage ossification produces hypoplastic ilia with the diagnostic snail-like projection.

Advanced Tarsal Ossification Disordered endochondral ossification includes precocious tarsal ossification.

Show evidence (1 reference)

PMID:19508970 SUPPORT Human Clinical

"severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies"

Human radiology supports axial ossification failure in Schneckenbecken dysplasia.

Appendicular Skeletal Shortening and Metaphyseal Expansion

Defective chondroitin sulfate proteoglycan matrix in limb growth plates impairs longitudinal skeletal growth and metaphyseal modeling. Complete loss-of-function causes lethal micromelia with short broad dumbbell-shaped long bones, while hypomorphic SLC35D1 variants cause surviving short stature, mesomelia, genu valgum, and lower-extremity shortening.

Growth Plate Chondrocyte link

skeletal system development link cartilage development involved in endochondral bone morphogenesis link

Downstream

Severe Micromelia Failed limb growth plate function causes marked micromelia in lethal cases.

Dumbbell-Shaped Long Bones Abnormal metaphyseal modeling produces short broad long bones with a dumbbell contour.

Short Stature Partial loss of transporter function can preserve survival but impair longitudinal growth.

Mesomelia Hypomorphic SLC35D1 variants can preferentially shorten intermediate limb segments.

Genu Valgum Abnormal lower-extremity growth and metaphyseal modeling can produce genu valgum.

Show evidence (2 references)

PMID:17952091 SUPPORT Model Organism

"Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"

Mouse-model evidence supports severe appendicular shortening after Slc35d1 loss.

PMID:35934917 SUPPORT Human Clinical

"The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."

Human hypomorphic SLC35D1 variants support a milder surviving appendicular skeletal branch.

Thoracic Restriction and Pulmonary Hypoplasia

Rib and axial skeletal dysplasia produce a short, narrow, bell-shaped thorax. In the severe fetal phenotype, this constrained thoracic cage limits fetal lung expansion and is associated with pulmonary hypoplasia at autopsy.

Growth Plate Chondrocyte link

lung development link bone development link

Downstream

Bell-Shaped Thorax Short ribs and axial skeletal dysplasia produce a narrow bell-shaped thorax.

Pulmonary Hypoplasia Severe thoracic restriction is associated with pulmonary hypoplasia in lethal fetal cases.

Show evidence (2 references)

PMID:19508970 SUPPORT Human Clinical

"The chest was narrow and bell shaped."

Human fetal radiology supports the thoracic restriction branch.

PMID:19508970 SUPPORT Human Clinical

"The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"

Autopsy evidence supports pulmonary hypoplasia in severe disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

18

Head and Neck 2

Short Neck Short neck (HP:0000470)

Show evidence (2 references)

PMID:19508970 SUPPORT Human Clinical

"On prenatal ultrasound at 22 weeks gestation, this fetus was identified as having a short neck with redundant nuchal skin, narrow thorax, scoliosis, and short limbs"

Detailed prenatal case description documents short neck as part of the fetal presentation.

PMID:25997753 SUPPORT Human Clinical

"Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."

Published phenotype summaries of classic Schneckenbecken dysplasia include short neck among the recognizable prenatal findings.

Flat Midface Midface retrusion (HP:0011800)

Show evidence (1 reference)

PMID:25997753 SUPPORT Human Clinical

"Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."

Published phenotype summaries identify a very flat midface as part of the classic craniofacial phenotype.

Limbs 4

Severe Micromelia Micromelia (HP:0002983)

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"short, broad long-bones with dumbbell-like appearance; short and wide fibula"

Original description documents severe limb shortening with characteristic dumbbell-shaped long bones.

PMID:19508970 SUPPORT Human Clinical

"There was marked micromelia."

Multi-family case descriptions document marked micromelia in the classic prenatal lethal phenotype.

Dumbbell-Shaped Long Bones Dumbbell-shaped long bone (HP:0000947)

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"short, broad long-bones with dumbbell-like appearance"

Original description identifies the dumbbell-like long bone morphology.

PMID:35934917 SUPPORT Human Clinical

"short and broad long bones with a dumbbell-like appearance, thoracic hypoplasia"

Later report confirms dumbbell-shaped long bones as characteristic even in milder cases.

Brachydactyly Brachydactyly (HP:0001156)

Show evidence (1 reference)

PMID:25997753 SUPPORT Human Clinical

"Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."

Review of the published Schneckenbecken dysplasia phenotype spectrum includes brachydactyly among the recurring skeletal findings.

Genu Valgum Genu valgum (HP:0002857)

Show evidence (1 reference)

PMID:35934917 SUPPORT Human Clinical

"The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."

Genu valgum is explicitly reported in the surviving hypomorphic SLC35D1 phenotype.

Metabolism 1

Hydrops Fetalis Hydrops fetalis (HP:0001789)

Show evidence (2 references)

PMID:11200994 SUPPORT Human Clinical

"this is the first report of Schneckenbecken dysplasia with the development of hydrops early in the second trimester"

Documents hydrops fetalis developing in the second trimester in a confirmed case.

PMID:19508970 SUPPORT Human Clinical

"This fetus was identified on 18 weeks ultrasound as having hydrops and short limbs"

Additional case with hydrops detected on prenatal ultrasound.

Musculoskeletal 3

Severe Platyspondyly Platyspondyly (HP:0000926)

Show evidence (3 references)

PMID:3799723 SUPPORT Human Clinical

"flattened, hypoplastic vertebral bodies"

Original description documents severely flattened vertebral bodies as a characteristic radiographic feature.

PMID:19508970 SUPPORT Human Clinical

"severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies"

Multi-family study confirms severe platyspondyly with deficient posterior ossification as a hallmark feature.

PMID:1754916 SUPPORT Human Clinical

"demonstrating a short-limbed, platyspondylic dwarf with a snail-like configuration of the ilium and vertebral bodies, flat on AP and round on lateral view"

Follow-up case report confirms platyspondyly with the characteristic flattened AP and rounded lateral vertebral contour.

Hypoplastic Ilia with Snail-Like Configuration Hypoplastic ilia (HP:0000946)

Show evidence (3 references)

PMID:3799723 SUPPORT Human Clinical

"hypoplastic iliac bones with "a snail-like" configuration"

Original description identifies the snail-like iliac configuration as pathognomonic.

PMID:19508970 SUPPORT Human Clinical

"The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone"

Confirms that the snail-like iliac configuration is the radiological hallmark.

PMID:19407457 SUPPORT Human Clinical

"showing especially the small ilia with medial snail-like projection"

Additional fetal series confirms the characteristic medial iliac projection.

Short Ribs Short ribs (HP:0000773)

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"short ribs"

Original description identifies short ribs as a cardinal feature.

PMID:25997753 SUPPORT Human Clinical

"included midface hypoplasia, handlebar clavicles, short ribs, hypoplastic vertebrae with rounded anterior ends, short long bones with widened metaphyseal ends and a snail-like medial projection in the ileum"

INPPL1-related Schneckenbecken dysplasia preserves the characteristic short-rib phenotype seen in SLC35D1-related disease.

Prenatal and Birth 1

Polyhydramnios Polyhydramnios (HP:0001561)

Show evidence (1 reference)

PMID:25997753 SUPPORT Human Clinical

"Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."

Published phenotype summaries describe polyhydramnios as a recurrent pregnancy finding in Schneckenbecken dysplasia.

Respiratory 1

Pulmonary Hypoplasia Pulmonary hypoplasia (HP:0002089)

Show evidence (1 reference)

PMID:19508970 SUPPORT Human Clinical

"The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"

Autopsy confirmation of pulmonary hypoplasia in a classic case.

Growth 1

Short Stature Short stature (HP:0004322)

Show evidence (2 references)

PMID:35934917 SUPPORT Human Clinical

"The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."

Hypomorphic SLC35D1 variants can cause a surviving phenotype centered on short stature rather than perinatal lethality.

PMID:38058750 SUPPORT Human Clinical

"A 17-year-old male with a coarse face and short stature was referred to our clinic."

Independent report confirms short stature in the nonlethal SLC35D1 phenotypic spectrum.

Other 5

Bell-Shaped Thorax Bell-shaped thorax (HP:0001591)

Show evidence (1 reference)

PMID:19508970 SUPPORT Human Clinical

"The chest was narrow and bell shaped."

Bell-shaped thoracic constriction was documented radiographically in a molecularly supported fetal case.

Advanced Tarsal Ossification Advanced tarsal ossification (HP:0008108)

Show evidence (2 references)

PMID:3799723 SUPPORT Human Clinical

"precocious ossification of the tarsus"

Original description identifies precocious tarsal ossification as a distinguishing feature.

PMID:19508970 SUPPORT Human Clinical

"Tarsal ossification was advanced"

Confirmed in subsequent multi-family study.

Increased Nuchal Thickness Thickened nuchal skin fold (HP:0000474)

Show evidence (2 references)

PMID:15386610 SUPPORT Human Clinical

"presenting antenatally with increased nuchal thickness and severe skeletal dysplasia"

Prenatal case report identifies increased nuchal thickness as an early sonographic clue.

PMID:19508970 SUPPORT Human Clinical

"The fetus was terminated 20 weeks gestation due to detection of short limbs, redundant nuchal skin and scalp oedema on prenatal ultrasound."

Additional fetal case supports redundant nuchal soft tissue swelling within the prenatal phenotype spectrum.

Protuberant Abdomen Protuberant abdomen (HP:0001538)

Show evidence (1 reference)

PMID:19508970 SUPPORT Human Clinical

"The chest was narrow and short with a protuberant abdomen."

Detailed fetal case descriptions document a recurrent protuberant abdominal contour.

Mesomelia Mesomelia (HP:0003027)

Show evidence (1 reference)

PMID:35934917 SUPPORT Human Clinical

"The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."

Mild mesomelia is part of the documented nonlethal spectrum caused by hypomorphic SLC35D1 variants.

🧬

Genetic Associations

2

SLC35D1 Loss-of-Function Mutations (Causative)

Show evidence (6 references)

PMID:17952091 SUPPORT Human Clinical

"We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia"

Initial identification of SLC35D1 as the causative gene through combined human and mouse genetic studies.

PMID:19508970 SUPPORT Human Clinical

"We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families"

Documents the spectrum of SLC35D1 loss-of-function mutations in multiple families from different ethnic backgrounds.

PMID:19508970 SUPPORT Human Clinical

"Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD"

Demonstrates that SLC35D1 mutations are specific to Schneckenbecken dysplasia within the severe spondylodysplastic dysplasias group.

+ 3 more references

INPPL1 Mutations (Second Locus) (Causative)

Show evidence (1 reference)

PMID:25997753 SUPPORT Human Clinical

"apparent loss of INPPL1 function can produce either the perinatal lethal Schneckenbecken dysplasia phenotype or non-lethal opsismodysplasia"

Identifies INPPL1 as a second locus for Schneckenbecken dysplasia with an allelic spectrum including opsismodysplasia.

💊

Treatments

1

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is recommended for families with an affected pregnancy given the autosomal recessive inheritance pattern and observed consanguinity in many reported families. Prenatal molecular testing is available when familial mutations are known.

🔬

Biochemical Markers

1

Deficient Chondroitin Sulfate Biosynthesis

Pathograph Readouts

Readout Of Defective Nucleotide-Sugar Transport Negative Diagnostic

Short, sparse chondroitin sulfate chains report impaired SLC35D1-dependent nucleotide-sugar transport into the ER.

Show evidence (1 reference)

PMID:17952091 SUPPORT Model Organism

"These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"

The model directly supports reduced chondroitin sulfate chains as a readout of the upstream transport defect.

Readout Of Deficient Chondroitin Sulfate Proteoglycan Matrix Negative Diagnostic

Reduced chondroitin sulfate chain abundance and length reports the cartilage proteoglycan matrix defect.

Show evidence (1 reference)

PMID:17952091 SUPPORT Model Organism

"Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"

Reduced proteoglycan aggregates and scarce matrix support this biochemical readout of the matrix branch.

Show evidence (2 references)

PMID:17952091 SUPPORT Model Organism

"These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"

Direct biochemical demonstration of defective chondroitin sulfate chain synthesis in the mouse model.

PMID:31423530 SUPPORT In Vitro

"The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum"

Demonstrates that SLC35D1 is a general UDP-sugar transporter, suggesting the biochemical defect may extend beyond chondroitin sulfate.

{ }

Source YAML

click to show

name: Schneckenbecken Dysplasia
creation_date: "2026-04-02T00:00:00Z"
updated_date: "2026-05-19T06:06:31Z"
category: Mendelian
description: >
  Schneckenbecken dysplasia is a perinatally lethal autosomal recessive skeletal dysplasia
  classified in the severe spondylodysplastic dysplasias group. The name derives from the
  German word for "snail pelvis," referring to the characteristic snail-like configuration of
  the hypoplastic iliac bones on radiography. The disorder is caused by biallelic
  loss-of-function mutations in SLC35D1, encoding an endoplasmic reticulum nucleotide-sugar
  transporter critical for chondroitin sulfate biosynthesis in cartilage proteoglycans. A
  second locus (INPPL1) has been identified in rare cases. Cardinal features include severe
  platyspondyly, short ribs with narrow thorax, markedly shortened long bones with
  dumbbell-shaped appearance, and precocious tarsal ossification. Histology reveals
  hypercellular and hypervascular cartilage with loss of columnar chondrocyte organization
  in the growth plate. Death occurs in utero or shortly after birth, typically from
  pulmonary hypoplasia secondary to thoracic restriction. Hypomorphic SLC35D1 alleles can
  produce a milder, nonlethal phenotype with short stature and skeletal anomalies,
  indicating a phenotypic spectrum.
disease_term:
  preferred_term: schneckenbecken dysplasia
  term:
    id: MONDO:0010013
    label: schneckenbecken dysplasia
parents:
- Lethal Skeletal Dysplasia
- Spondylodysplastic Dysplasia
- Congenital Disorder of Glycosylation
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    All confirmed cases with SLC35D1 mutations have been homozygous or compound
    heterozygous for loss-of-function alleles. Multiple reports describe consanguineous
    parents, consistent with autosomal recessive inheritance. The original description
    documented autosomal recessive inheritance in affected families.
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a distinct neonatal lethal chondrodysplasia inherited as an autosomal recessive trait"
    explanation: Original description establishes autosomal recessive inheritance pattern.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias"
    explanation: Confirms autosomal recessive inheritance and nosology classification.
prevalence:
- population: Global
  percentage: Unknown
  notes: >-
    Schneckenbecken dysplasia is ultra-rare. Fewer than 20 families have been
    reported in the literature since the original description in 1986. The
    disorder appears to occur across multiple ethnic backgrounds, with cases
    reported in families of Caucasian, Turkish, Brazilian, and Mediterranean
    origin. No population-based prevalence estimates are available.
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases"
    explanation: Study of five SBD families indicates ultra-rare prevalence globally.
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only six cases with homozygous SLC35D1 variants have been reported to date"
    explanation: As of 2022, only six molecularly confirmed cases had been reported, underscoring the ultra-rare nature.
pathophysiology:
- name: Defective Nucleotide-Sugar Transport
  description: >
    SLC35D1 encodes an endoplasmic reticulum nucleotide-sugar transporter that
    transports UDP-glucuronic acid and UDP-N-acetylgalactosamine from the cytoplasm
    into the ER lumen. These substrates are required for chondroitin sulfate
    biosynthesis. Loss-of-function mutations abolish transporter activity, leading to
    defective chondroitin sulfate chain synthesis on cartilage proteoglycan core proteins.
    The resulting proteoglycans have short, sparse chondroitin sulfate chains that cannot
    maintain normal cartilage extracellular matrix integrity.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Nucleotide-Sugar Transmembrane Transport
    term:
      id: GO:0015780
      label: nucleotide-sugar transmembrane transport
  - preferred_term: Chondroitin Sulfate Proteoglycan Biosynthesis
    term:
      id: GO:0050650
      label: chondroitin sulfate proteoglycan biosynthetic process
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"
    explanation: Slc35d1 knockout mice recapitulate the lethal skeletal dysplasia phenotype, confirming the gene's role in skeletal development.
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"
    explanation: Demonstrates that SLC35D1 deficiency directly impairs chondroitin sulfate chain formation.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars"
    explanation: Functional assay demonstrates that the disease-causing missense mutation abolishes nucleotide-sugar transport activity.
  downstream:
  - target: Deficient Chondroitin Sulfate Proteoglycan Matrix
    causal_link_type: DIRECT
    description: >-
      Loss of SLC35D1 nucleotide-sugar transport limits ER-luminal substrates for
      chondroitin sulfate synthesis, producing shortened and sparse
      chondroitin sulfate chains on cartilage proteoglycans.
    evidence:
    - reference: PMID:17952091
      reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"
      explanation: The Slc35d1 knockout directly links transporter loss to shortened, sparse chondroitin sulfate chains.
- name: Deficient Chondroitin Sulfate Proteoglycan Matrix
  description: >
    Defective chondroitin sulfate biosynthesis reduces both the length and number
    of chondroitin sulfate chains on cartilage proteoglycans. The resulting
    extracellular matrix contains reduced proteoglycan aggregates and cannot
    support normal growth plate organization, chondrocyte column formation, or
    endochondral skeletal morphogenesis.
  cell_types:
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: cartilage development involved in endochondral bone morphogenesis
    term:
      id: GO:0060351
      label: cartilage development involved in endochondral bone morphogenesis
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"
    explanation: The mouse model demonstrates deficient chondroitin sulfate chain synthesis as the primary matrix defect.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological findings in SBD include large, round, and centrally located chondrocyte nuclei, scarce extracellular matrix, and an absence of columnar alignment of proliferating chondrocytes in the growth plate."
    explanation: Human histopathology supports scarce cartilage extracellular matrix with disrupted chondrocyte columns.
  downstream:
  - target: Growth Plate Disorganization
    causal_link_type: DIRECT
    description: >-
      Reduced proteoglycan aggregate formation disrupts cartilage matrix
      integrity, producing the disorganized proliferating zone and abnormal
      chondrocyte morphology seen in the growth plate.
    evidence:
    - reference: PMID:17952091
      reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"
      explanation: The Slc35d1 knockout links reduced proteoglycan aggregates and scarce matrix to growth plate disorganization.
- name: Growth Plate Disorganization
  description: >
    Loss of functional chondroitin sulfate proteoglycans in the cartilage matrix disrupts
    the normal architecture of the epiphyseal growth plate. The proliferating zone is
    decreased, columnar alignment of chondrocytes is absent, and the extracellular matrix
    is scarce. Chondrocytes are round with centrally located nuclei and lack normal lacunar
    spaces. The cartilage is hypercellular and hypervascular. These changes severely impair
    endochondral ossification, resulting in the characteristic skeletal anomalies.
  cell_types:
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Cartilage Development in Endochondral Bone Formation
    term:
      id: GO:0060351
      label: cartilage development involved in endochondral bone morphogenesis
  - preferred_term: Chondrocyte Differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"
    explanation: Mouse model demonstrates growth plate disorganization with decreased proliferation, round chondrocytes, and depleted matrix.
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chondro-osseous histology is characteristic with hypervascularity, increased cellular density, and normal size chondrocytes with a centrally located round nucleus and absence of lacunar space"
    explanation: Original human histopathology description confirms characteristic growth plate findings.
  - reference: PMID:11200994
    reference_title: "Schneckenbecken dysplasia, radiology, and histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histology showed hypercellular and hypervascular cartilage with chondrocytes with centrally located nucleus"
    explanation: Additional human case confirms the characteristic cartilage histology with hypercellularity and hypervascularization.
  downstream:
  - target: Vertebral and Pelvic Ossification Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Failed endochondral ossification in axial and pelvic cartilage templates.
    description: >-
      Disorganized growth plate cartilage impairs vertebral and pelvic
      ossification, producing platyspondyly and the characteristic hypoplastic
      snail-like ilia.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other skeletal hallmarks of SBD include thoracic hypoplasia, severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies, and short thick long bones."
      explanation: Human radiology links SBD growth-plate pathology to severe vertebral ossification failure and skeletal malformation.
  - target: Appendicular Skeletal Shortening and Metaphyseal Expansion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired longitudinal growth and metaphyseal modeling at endochondral growth plates.
    description: >-
      Abnormal cartilage matrix and chondrocyte organization impair limb growth,
      causing micromelia, dumbbell-shaped long bones, and milder surviving limb
      phenotypes when transporter activity is partially retained.
    evidence:
    - reference: PMID:17952091
      reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"
      explanation: The model links Slc35d1 deficiency and growth plate pathology to severe appendicular skeletal shortening.
  - target: Thoracic Restriction and Pulmonary Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Short ribs and narrow thoracic cage restrict fetal lung growth.
    description: >-
      Endochondral skeletal dysplasia affects ribs and the thoracic cage,
      producing a narrow bell-shaped thorax that can secondarily impair fetal
      lung expansion and cause pulmonary hypoplasia.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"
      explanation: Human autopsy data support pulmonary hypoplasia in severe Schneckenbecken dysplasia with thoracic restriction.
  - target: Short Ribs
    causal_link_type: DIRECT
    description: Rib growth plate disorganization produces short ribs as part of the lethal skeletal dysplasia pattern.
    evidence:
    - reference: PMID:3799723
      reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "short ribs"
      explanation: The original description directly supports short ribs downstream of skeletal growth plate pathology.
- name: Vertebral and Pelvic Ossification Failure
  description: >
    Severe growth plate disorganization and defective endochondral ossification
    produce axial and pelvic skeletal abnormalities: flattened vertebral bodies,
    delayed posterior vertebral ossification, hypoplastic ilia with a medial
    snail-like projection, and abnormal timing of tarsal ossification.
  cell_types:
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: bone development
    term:
      id: GO:0060348
      label: bone development
  - preferred_term: cartilage development involved in endochondral bone morphogenesis
    term:
      id: GO:0060351
      label: cartilage development involved in endochondral bone morphogenesis
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies"
    explanation: Human radiology supports axial ossification failure in Schneckenbecken dysplasia.
  downstream:
  - target: Severe Platyspondyly
    causal_link_type: DIRECT
    description: Failed vertebral body ossification manifests as severe platyspondyly.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies"
      explanation: The radiographic description directly supports platyspondyly downstream of axial ossification failure.
  - target: Hypoplastic Ilia with Snail-Like Configuration
    causal_link_type: DIRECT
    description: Defective pelvic cartilage ossification produces hypoplastic ilia with the diagnostic snail-like projection.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone"
      explanation: The SBD radiological hallmark directly supports the pelvic phenotype.
  - target: Advanced Tarsal Ossification
    causal_link_type: DIRECT
    description: Disordered endochondral ossification includes precocious tarsal ossification.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tarsal ossification was advanced"
      explanation: Human fetal radiology supports advanced tarsal ossification in the skeletal branch.
- name: Appendicular Skeletal Shortening and Metaphyseal Expansion
  description: >
    Defective chondroitin sulfate proteoglycan matrix in limb growth plates
    impairs longitudinal skeletal growth and metaphyseal modeling. Complete
    loss-of-function causes lethal micromelia with short broad dumbbell-shaped
    long bones, while hypomorphic SLC35D1 variants cause surviving short stature,
    mesomelia, genu valgum, and lower-extremity shortening.
  cell_types:
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  - preferred_term: cartilage development involved in endochondral bone morphogenesis
    term:
      id: GO:0060351
      label: cartilage development involved in endochondral bone morphogenesis
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"
    explanation: Mouse-model evidence supports severe appendicular shortening after Slc35d1 loss.
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
    explanation: Human hypomorphic SLC35D1 variants support a milder surviving appendicular skeletal branch.
  downstream:
  - target: Severe Micromelia
    causal_link_type: DIRECT
    description: Failed limb growth plate function causes marked micromelia in lethal cases.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There was marked micromelia."
      explanation: The clinical series directly supports severe micromelia.
  - target: Dumbbell-Shaped Long Bones
    causal_link_type: DIRECT
    description: Abnormal metaphyseal modeling produces short broad long bones with a dumbbell contour.
    evidence:
    - reference: PMID:3799723
      reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "short, broad long-bones with dumbbell-like appearance"
      explanation: The original human description supports dumbbell-shaped long bones.
  - target: Short Stature
    causal_link_type: DIRECT
    description: Partial loss of transporter function can preserve survival but impair longitudinal growth.
    evidence:
    - reference: PMID:35934917
      reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
      explanation: The milder human pedigree supports short stature as part of the hypomorphic appendicular branch.
  - target: Mesomelia
    causal_link_type: DIRECT
    description: Hypomorphic SLC35D1 variants can preferentially shorten intermediate limb segments.
    evidence:
    - reference: PMID:35934917
      reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
      explanation: The milder human pedigree explicitly supports mesomelia.
  - target: Genu Valgum
    causal_link_type: DIRECT
    description: Abnormal lower-extremity growth and metaphyseal modeling can produce genu valgum.
    evidence:
    - reference: PMID:35934917
      reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
      explanation: The milder human pedigree explicitly supports genu valgum.
- name: Thoracic Restriction and Pulmonary Hypoplasia
  description: >
    Rib and axial skeletal dysplasia produce a short, narrow, bell-shaped thorax.
    In the severe fetal phenotype, this constrained thoracic cage limits fetal
    lung expansion and is associated with pulmonary hypoplasia at autopsy.
  cell_types:
  - preferred_term: Growth Plate Chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: lung development
    term:
      id: GO:0030324
      label: lung development
  - preferred_term: bone development
    term:
      id: GO:0060348
      label: bone development
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The chest was narrow and bell shaped."
    explanation: Human fetal radiology supports the thoracic restriction branch.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"
    explanation: Autopsy evidence supports pulmonary hypoplasia in severe disease.
  downstream:
  - target: Bell-Shaped Thorax
    causal_link_type: DIRECT
    description: Short ribs and axial skeletal dysplasia produce a narrow bell-shaped thorax.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The chest was narrow and bell shaped."
      explanation: The clinical series directly supports the bell-shaped thorax phenotype.
  - target: Pulmonary Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Restricted fetal thoracic cage limits lung expansion.
    description: Severe thoracic restriction is associated with pulmonary hypoplasia in lethal fetal cases.
    evidence:
    - reference: PMID:19508970
      reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"
      explanation: Autopsy evidence directly supports pulmonary hypoplasia in severe Schneckenbecken dysplasia.
phenotypes:
- category: Skeletal
  name: Severe Platyspondyly
  description: >
    Marked flattening of the vertebral bodies is a core radiographic feature. In classic
    lethal cases the vertebral bodies can be wafer-thin, with deficient ossification of the
    posterior elements and a rounded profile on lateral radiographs.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flattened, hypoplastic vertebral bodies"
    explanation: Original description documents severely flattened vertebral bodies as a characteristic radiographic feature.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe flattening of the vertebral bodies with absent ossification of the posterior parts of the vertebral bodies"
    explanation: Multi-family study confirms severe platyspondyly with deficient posterior ossification as a hallmark feature.
  - reference: PMID:1754916
    reference_title: "Case report 693: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "demonstrating a short-limbed, platyspondylic dwarf with a snail-like configuration of the ilium and vertebral bodies, flat on AP and round on lateral view"
    explanation: Follow-up case report confirms platyspondyly with the characteristic flattened AP and rounded lateral vertebral contour.
- category: Skeletal
  name: Hypoplastic Ilia with Snail-Like Configuration
  description: >
    The iliac bones are hypoplastic with a distinctive medial bone projection from the
    inner iliac margin, producing the pathognomonic snail-like (Schneckenbecken)
    appearance on anteroposterior pelvic radiographs. This is the defining feature
    from which the disorder derives its name.
  phenotype_term:
    preferred_term: Hypoplastic ilia
    term:
      id: HP:0000946
      label: Hypoplastic ilia
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplastic iliac bones with \"a snail-like\" configuration"
    explanation: Original description identifies the snail-like iliac configuration as pathognomonic.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone"
    explanation: Confirms that the snail-like iliac configuration is the radiological hallmark.
  - reference: PMID:19407457
    reference_title: "Schneckenbecken dysplasia in fetus: report of four cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showing especially the small ilia with medial snail-like projection"
    explanation: Additional fetal series confirms the characteristic medial iliac projection.
- category: Skeletal
  name: Severe Micromelia
  description: >
    The appendicular skeleton is markedly shortened in the classic lethal phenotype. Long
    bones are short and broad, and the fibula can also be short and wide.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short, broad long-bones with dumbbell-like appearance; short and wide fibula"
    explanation: Original description documents severe limb shortening with characteristic dumbbell-shaped long bones.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was marked micromelia."
    explanation: Multi-family case descriptions document marked micromelia in the classic prenatal lethal phenotype.
- category: Skeletal
  name: Dumbbell-Shaped Long Bones
  description: >
    Long bones are short and broad with relative metaphyseal expansion, producing a
    dumbbell-like contour on radiographs.
  phenotype_term:
    preferred_term: Dumbbell-shaped long bone
    term:
      id: HP:0000947
      label: Dumbbell-shaped long bone
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short, broad long-bones with dumbbell-like appearance"
    explanation: Original description identifies the dumbbell-like long bone morphology.
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short and broad long bones with a dumbbell-like appearance, thoracic hypoplasia"
    explanation: Later report confirms dumbbell-shaped long bones as characteristic even in milder cases.
- category: Skeletal
  name: Short Ribs
  description: >
    Short ribs are part of the characteristic lethal skeletal dysplasia pattern and
    contribute to thoracic restriction.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short ribs"
    explanation: Original description identifies short ribs as a cardinal feature.
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "included midface hypoplasia, handlebar clavicles, short ribs, hypoplastic vertebrae with rounded anterior ends, short long bones with widened metaphyseal ends and a snail-like medial projection in the ileum"
    explanation: INPPL1-related Schneckenbecken dysplasia preserves the characteristic short-rib phenotype seen in SLC35D1-related disease.
- category: Skeletal
  name: Bell-Shaped Thorax
  description: >
    The thorax is narrow and bell shaped in the classic lethal presentation, reflecting
    severe thoracic constriction.
  phenotype_term:
    preferred_term: Bell-shaped thorax
    term:
      id: HP:0001591
      label: Bell-shaped thorax
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The chest was narrow and bell shaped."
    explanation: Bell-shaped thoracic constriction was documented radiographically in a molecularly supported fetal case.
- category: Skeletal
  name: Advanced Tarsal Ossification
  description: >
    Advanced ossification of the tarsal bones is a distinctive radiographic finding
    that distinguishes Schneckenbecken dysplasia from other severe spondylodysplastic
    dysplasias.
  phenotype_term:
    preferred_term: Advanced tarsal ossification
    term:
      id: HP:0008108
      label: Advanced tarsal ossification
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "precocious ossification of the tarsus"
    explanation: Original description identifies precocious tarsal ossification as a distinguishing feature.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tarsal ossification was advanced"
    explanation: Confirmed in subsequent multi-family study.
- category: Skeletal
  name: Brachydactyly
  description: >
    Short digits have been included among the recurring skeletal findings of classic
    Schneckenbecken dysplasia.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."
    explanation: Review of the published Schneckenbecken dysplasia phenotype spectrum includes brachydactyly among the recurring skeletal findings.
- category: Skeletal
  name: Short Neck
  description: >
    Prenatal ultrasound may show a short neck, sometimes with associated redundant nuchal
    skin.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On prenatal ultrasound at 22 weeks gestation, this fetus was identified as having a short neck with redundant nuchal skin, narrow thorax, scoliosis, and short limbs"
    explanation: Detailed prenatal case description documents short neck as part of the fetal presentation.
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."
    explanation: Published phenotype summaries of classic Schneckenbecken dysplasia include short neck among the recognizable prenatal findings.
- category: Craniofacial
  name: Flat Midface
  description: >
    A very flat or retrusive midface has been described in classic cases and contributes to
    the characteristic craniofacial appearance.
  phenotype_term:
    preferred_term: Flat midface
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."
    explanation: Published phenotype summaries identify a very flat midface as part of the classic craniofacial phenotype.
- category: Prenatal
  name: Increased Nuchal Thickness
  description: >
    Increased nuchal thickness or redundant nuchal skin can be one of the earliest prenatal
    clues, sometimes noted together with generalized fetal edema.
  phenotype_term:
    preferred_term: Increased nuchal thickness
    term:
      id: HP:0000474
      label: Thickened nuchal skin fold
  evidence:
  - reference: PMID:15386610
    reference_title: "Perinatally lethal, short-limbed dwarfism with distinct features -- Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting antenatally with increased nuchal thickness and severe skeletal dysplasia"
    explanation: Prenatal case report identifies increased nuchal thickness as an early sonographic clue.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus was terminated 20 weeks gestation due to detection of short limbs, redundant nuchal skin and scalp oedema on prenatal ultrasound."
    explanation: Additional fetal case supports redundant nuchal soft tissue swelling within the prenatal phenotype spectrum.
- category: Prenatal
  name: Polyhydramnios
  description: >
    Polyhydramnios has been reported in affected pregnancies and is part of the prenatal
    phenotype spectrum.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings include relative macrocephaly, a very flat midface, cleft palate, a short neck, a narrow thorax, brachydactyly, and a high incidence of polyhydramnios."
    explanation: Published phenotype summaries describe polyhydramnios as a recurrent pregnancy finding in Schneckenbecken dysplasia.
- category: Prenatal
  name: Hydrops Fetalis
  description: >
    Nonimmune hydrops fetalis has been reported in multiple cases, sometimes developing
    as early as the second trimester. Associated findings include cystic hygroma,
    scalp edema, and placental hydropic changes.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:11200994
    reference_title: "Schneckenbecken dysplasia, radiology, and histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this is the first report of Schneckenbecken dysplasia with the development of hydrops early in the second trimester"
    explanation: Documents hydrops fetalis developing in the second trimester in a confirmed case.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This fetus was identified on 18 weeks ultrasound as having hydrops and short limbs"
    explanation: Additional case with hydrops detected on prenatal ultrasound.
- category: Abdominal
  name: Protuberant Abdomen
  description: >
    A protuberant abdomen has been described repeatedly in fetuses with the classic lethal
    phenotype.
  phenotype_term:
    preferred_term: Protuberant abdomen
    term:
      id: HP:0001538
      label: Protuberant abdomen
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The chest was narrow and short with a protuberant abdomen."
    explanation: Detailed fetal case descriptions document a recurrent protuberant abdominal contour.
- category: Respiratory
  name: Pulmonary Hypoplasia
  description: >
    Pulmonary hypoplasia has been documented at autopsy in classic cases and likely reflects
    severe thoracic restriction.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy revealed placental hydropic changes, pulmonary hypoplasia and accessory spleen"
    explanation: Autopsy confirmation of pulmonary hypoplasia in a classic case.
- category: Growth
  name: Short Stature
  description: >
    Surviving individuals with hypomorphic SLC35D1 variants can present with nonlethal
    short stature rather than the classic perinatal lethal phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
    explanation: Hypomorphic SLC35D1 variants can cause a surviving phenotype centered on short stature rather than perinatal lethality.
  - reference: PMID:38058750
    reference_title: "A Mild Skeletal Dysplasia Caused by a Biallelic Missense Variant in the SLC35D1 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 17-year-old male with a coarse face and short stature was referred to our clinic."
    explanation: Independent report confirms short stature in the nonlethal SLC35D1 phenotypic spectrum.
- category: Skeletal
  name: Mesomelia
  description: >
    Mild mesomelia has been reported in the nonlethal hypomorphic SLC35D1 spectrum.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
    explanation: Mild mesomelia is part of the documented nonlethal spectrum caused by hypomorphic SLC35D1 variants.
- category: Skeletal
  name: Genu Valgum
  description: >
    Genu valgum is part of the limb phenotype in some surviving individuals with
    hypomorphic SLC35D1 variants.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax."
    explanation: Genu valgum is explicitly reported in the surviving hypomorphic SLC35D1 phenotype.
genetic:
- name: SLC35D1 Loss-of-Function Mutations
  association: Causative
  gene_term:
    preferred_term: SLC35D1
    term:
      id: hgnc:20800
      label: SLC35D1
  features: >
    Biallelic loss-of-function mutations in SLC35D1 (1p31.3) are the primary cause.
    Identified mutations include nonsense mutations (p.R107X), splice site mutations
    (IVS4+3A>G), large deletions (exon 7 deletion), and missense mutations that
    abolish transporter activity (p.T65P). SLC35D1 encodes a nucleotide-sugar transporter
    in the endoplasmic reticulum membrane. Hypomorphic missense alleles (e.g. p.Pro133Leu,
    p.Met134Thr, p.Gly300Val) that reduce but do not abolish transport activity produce a
    milder nonlethal phenotype with short stature and skeletal anomalies.
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia"
    explanation: Initial identification of SLC35D1 as the causative gene through combined human and mouse genetic studies.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families"
    explanation: Documents the spectrum of SLC35D1 loss-of-function mutations in multiple families from different ethnic backgrounds.
  - reference: PMID:19508970
    reference_title: "Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD"
    explanation: Demonstrates that SLC35D1 mutations are specific to Schneckenbecken dysplasia within the severe spondylodysplastic dysplasias group.
  - reference: PMID:31423530
    reference_title: "A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity"
    explanation: Biochemical characterization shows that hypomorphic mutations reduce but do not abolish transport activity, correlating with milder phenotype.
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first case report of a family with a novel likely pathogenic variant (p. Met134Thr) and mild phenotypic features"
    explanation: Demonstrates the milder end of the SLC35D1 phenotypic spectrum with surviving patients showing short stature and mild skeletal anomalies.
  - reference: CGGV:assertion_4ee94dfc-b68e-4a26-ab68-7af456b9d826-2024-12-23T170000.000Z
    reference_title: "SLC35D1 / schneckenbecken dysplasia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC35D1 | HGNC:20800 | schneckenbecken dysplasia | MONDO:0010013 | AR | Definitive"
    explanation: ClinGen classifies the SLC35D1-schneckenbecken dysplasia gene-disease relationship as definitive with autosomal recessive inheritance.
- name: INPPL1 Mutations (Second Locus)
  association: Causative
  gene_term:
    preferred_term: INPPL1
    term:
      id: hgnc:6080
      label: INPPL1
  features: >
    Homozygous loss-of-function mutations in INPPL1, encoding inositol polyphosphate
    phosphatase-like 1, have been identified as a second locus for Schneckenbecken
    dysplasia. INPPL1 mutations can also cause the milder opsismodysplasia, indicating
    an allelic spectrum. The mechanism by which INPPL1 deficiency affects cartilage
    matrix is not fully characterized but may involve phosphatidylinositol signaling
    pathways relevant to matrix production.
  evidence:
  - reference: PMID:25997753
    reference_title: "A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apparent loss of INPPL1 function can produce either the perinatal lethal Schneckenbecken dysplasia phenotype or non-lethal opsismodysplasia"
    explanation: Identifies INPPL1 as a second locus for Schneckenbecken dysplasia with an allelic spectrum including opsismodysplasia.
animal_models:
- species: Mus musculus
  genotype: Slc35d1-/-
  description: >
    Slc35d1-deficient mice develop a lethal form of skeletal dysplasia with severe
    shortening of limbs and facial structures, closely recapitulating the human
    Schneckenbecken phenotype. Epiphyseal cartilage shows a decreased proliferating zone
    with round chondrocytes, scarce matrices, and reduced proteoglycan aggregates.
    Biochemical analysis revealed short, sparse chondroitin sulfate chains caused by
    defective chondroitin sulfate biosynthesis on cartilage proteoglycan core proteins.
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures"
    explanation: Mouse model faithfully recapitulates the lethal skeletal dysplasia phenotype observed in human Schneckenbecken dysplasia.
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"
    explanation: Growth plate histopathology in knockout mice mirrors human findings of disorganized cartilage.
biochemical:
- name: Deficient Chondroitin Sulfate Biosynthesis
  notes: >
    The primary biochemical defect is impaired transport of UDP-glucuronic acid and
    UDP-N-acetylgalactosamine into the endoplasmic reticulum lumen, leading to deficient
    chondroitin sulfate chain synthesis. Chondroitin sulfate chains on cartilage
    proteoglycan core proteins are shortened and reduced in number, compromising the
    structural and functional integrity of cartilage extracellular matrix. SLC35D1 also
    functions as a general UDP-sugar transporter, suggesting the defect may extend
    beyond chondroitin sulfate to other ER glycosylation reactions.
  readouts:
  - target: Defective Nucleotide-Sugar Transport
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Short, sparse chondroitin sulfate chains report impaired SLC35D1-dependent nucleotide-sugar transport into the ER.
    evidence:
    - reference: PMID:17952091
      reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"
      explanation: The model directly supports reduced chondroitin sulfate chains as a readout of the upstream transport defect.
  - target: Deficient Chondroitin Sulfate Proteoglycan Matrix
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced chondroitin sulfate chain abundance and length reports the cartilage proteoglycan matrix defect.
    evidence:
    - reference: PMID:17952091
      reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates"
      explanation: Reduced proteoglycan aggregates and scarce matrix support this biochemical readout of the matrix branch.
  evidence:
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis"
    explanation: Direct biochemical demonstration of defective chondroitin sulfate chain synthesis in the mouse model.
  - reference: PMID:31423530
    reference_title: "A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum"
    explanation: Demonstrates that SLC35D1 is a general UDP-sugar transporter, suggesting the biochemical defect may extend beyond chondroitin sulfate.
treatments:
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended for families with an affected pregnancy given
    the autosomal recessive inheritance pattern and observed consanguinity in many
    reported families. Prenatal molecular testing is available when familial mutations
    are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
has_subtypes:
- name: Classic Lethal
  description: >
    The classic perinatally lethal form caused by complete loss-of-function SLC35D1
    mutations. Presents with all cardinal features and results in death in utero or
    shortly after birth.
  evidence:
  - reference: PMID:3799723
    reference_title: "A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a distinct neonatal lethal chondrodysplasia inherited as an autosomal recessive trait"
    explanation: Original description of the classic lethal form with characteristic radiographic and histologic features.
  - reference: PMID:17952091
    reference_title: "Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia"
    explanation: Identifies complete loss-of-function SLC35D1 mutations as the cause of the classic lethal form.
- name: Mild Nonlethal
  display_name: Mild Nonlethal (Hypomorphic SLC35D1)
  description: >
    A milder form caused by hypomorphic missense SLC35D1 mutations that reduce but
    do not abolish transporter activity. Patients survive with short stature,
    mild mesomelia, genu valgum, and narrow thorax.
  evidence:
  - reference: PMID:35934917
    reference_title: "A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax"
    explanation: Describes the mild nonlethal phenotype in a large family with a hypomorphic SLC35D1 variant.
  - reference: PMID:38058750
    reference_title: "A Mild Skeletal Dysplasia Caused by a Biallelic Missense Variant in the SLC35D1 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our observation confirms the existence of nonlethal skeletal dysplasias associated with biallelic SLC35D1 variants and suggests the existence of a phenotypic spectrum"
    explanation: Independent confirmation of a phenotypic spectrum from lethal to mild skeletal dysplasia.
notes: >-
  Schneckenbecken dysplasia was first described by Borochowitz et al. in 1986 based on
  clinical, radiographic, and histopathologic features. The molecular basis was identified
  in 2007 when Hiraoka et al. linked biallelic SLC35D1 mutations to the disorder through
  combined human genetic studies and a knockout mouse model. The disorder belongs to the
  severe spondylodysplastic dysplasias group in the international skeletal dysplasia
  nosology, alongside achondrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian
  type, and fibrochondrogenesis. Notably, SLC35D1 mutations appear exclusive to
  Schneckenbecken dysplasia within this group. The identification of a second locus
  (INPPL1) in 2015 suggests genetic heterogeneity, with both loci potentially converging
  on cartilage extracellular matrix production. Prenatal diagnosis is possible through
  ultrasound detection of severe limb shortening and narrow thorax in the second trimester.

📚

References & Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schneckenbecken Dysplasia. Core disease mechanisms, molecular and cellular...

Asta Scientific Corpus Retrieval 19 citations 2026-04-02T22:49:11.704581

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schneckenbecken Dysplasia. Core disease mechanisms, molecular and cellular...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 19
Snippets retrieved: 20

Relevant Papers

[1] EndoCompass Project: Research Roadmap for Calcium and Bone Endocrinology

Authors: K. Jähn-Rickert, K. Z. Tomsic, A. Anastasilakis, Jean-Philippe Bertocchio, M. L. Brandi et al.
Year: 2025
Venue: Hormone Research in Pædiatrics
URL: https://www.semanticscholar.org/paper/fccbdcae3a86c448632e05f9c38ad2563c14284d
DOI: 10.1159/000549160
PMID: 41296665
PMCID: 12698132
Summary: This framework identifies crucial investigation areas into metabolic bone disease pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society.
Evidence snippets:
Snippet 1 (score: 0.430) > Skeletal dysplasias encompass a large spectrum of genetic disorders of the skeleton with abnormal bone growth, structure, or strength [85]. Individually, they are rare but, collectively, due to the large number of skeletal dysplasias (>700), they result in significant morbidity. The underlying pathology remains inadequately understood and the optimal therapy is often undefined, with precision drug treatment targeting the underlying molecular mechanism not available for most skeletal dysplasias. Gene discoveries have increased exponentially, demonstrating the value of advanced genetic tools and motivating further research into the complex pathogenesis of skeletal dysplasias. > However, further basic research is required to uncover the cellular pathology and implicated molecular pathways in various forms of skeletal dysplasia. Understanding the pathophysiology of skeletal dysplasias may also benefit a larger patient population. This is evidenced by anti-sclerostin treatment for osteoporosis [86] which, at present, is in clinical trials for osteogenesis imperfecta. Preclinical data show positive effects on bone mass and strength [87]. > The spectrum of disease manifestations of various skeletal dysplasias in different phases of life and health projections across the life course remain inadequately studied. Research on therapeutic approaches needs to focus not only on correcting the pathophysiology but also, more broadly, on surgical approaches, rehabilitation, functional/environmental adaptations, preventative measures, pain management, psychological support, and quality of life. Patient groups must be involved in identifying these research goals. International registries should be utilized to collect and analyse such data. > A multidisciplinary approach is of particular importance in genetic skeletal disorders, to enable cohesive care throughout the life course. The patients have a range of physical impairments due to their skeletal disorder, but also a disease-specific spectrum of extraskeletal manifestations requiring medical attention. These may include, for example, dental and oral health problems, immune deficiency, impaired hearing, and neurological or ophthalmologic manifestations.

[2] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.420) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Snippet 2 (score: 0.395) > The extensive clinical variability and genetic heterogeneity of GSDs, coupled with complex disease mechanisms, renders this extensive group of rare diseases a bench to bedside challenge. Indeed, this large number of different and highly complex phenotypes makes the identification, validation and development of potential therapies almost impossible for anything other than the most common GSDs. As an alternative approach, we might consider identifying genotype-and/or phenotype-independent 'core disease mechanisms' that are shared amongst families of clinically unrelated GSDs. This approach would allow the focusing of resources into several areas of concerted investigation that have the potential to identify and validate therapeutic targets with a broad application to GSDs, inherited connective tissues as a whole and rare genetic disease in general. Indeed, Jürgen Spranger first suggested the idea of 'bone dysplasia families' in 1985 [124] and proposed that phenotypes with a similar clinical and radiographic phenotype would likely have a similar disease mechanism. Thirty years later, we can now expand upon this pioneering concept and propose that common disease mechanisms can also be shared amongst clinically different phenotypes ('common amongst the rare'). > In this context, ER stress has been associated with a diverse range of genetic diseases and chronic conditions such as skeletal dysplasia (as discussed in this review), myopathy [125], cerebro-vascular [42], kidney [126], ischaemia and cardiovascular diseases [127]. Moreover, ER stress is emerging as a very attractive target that is being successfully exploited in a broad range of diseases including neuropathy, juvenile-onset openangle glaucoma, obesity, diabetes, asthma and epidermolysis bullosa, to name but a few. Historically many GSDs were considered diseases of the ECM and proposed therapeutic interventions involved the removal and/or correction of the relevant mutated gene or abnormal gene product. This was particularly the case with dominant-negative mutations in the large structural proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e.

[3] Clinical and Genetic Insights into Desbuquois Dysplasia: Review of 111 Case Reports

Authors: Hubert Piwar, M. Ordak, Magdalena Bujalska-Zadrożny
Year: 2024
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/49abd91511392c535dc098d7cfc55c4096c58c72
DOI: 10.3390/ijms25179700
PMID: 39273648
PMCID: 11395126
Citations: 4
Influential citations: 1
Summary: The review highlights the phenotypic variations across Desbuquois dysplasia subtypes, particularly in facial characteristics, joint dislocations, and bone deformities and underscores the importance of early diagnosis and the potential for personalized therapeutic approaches.
Evidence snippets:
Snippet 1 (score: 0.408) > The use of supraglottic devices, like the CobraPLA, may provide a viable alternative for maintaining a secure airway. However, the success of such devices may vary, and backup plans, including the use of advanced intubation techniques, should be prepared [54]. > This review highlights the significant variability in genetic mutations associated with Desbuquois dysplasia and their impact on clinical phenotypes. The predominance of DBQD1 cases in the literature suggests that further studies should investigate whether this reflects a true higher prevalence or whether it is a consequence of diagnostic biases. Additionally, the observation of developmental delays in a significant proportion of patients underscores the importance of early diagnosis and intervention. Future research should focus on several key areas: firstly, further studies are needed to deepen our understanding of the correlation between specific mutations and the clinical manifestations of Desbuquois dysplasia, which could help to refine the diagnostic criteria and improve prognostic predictions. Secondly, investigating the pathogenic pathways involving CANT1 and other relevant genes in Desbuquois dysplasia, particularly in comparison with their roles in other conditions, such as cancers, could uncover new insights into the disease's underlying mechanisms and identify potential biomarkers for earlier diagnosis or predicting disease progression. Thirdly, given the phenotypic variability observed among patients, there is a need for personalized therapeutic strategies that are tailored to individual clinical profiles. Future research should explore the potential for developing targeted therapies, such as enzyme replacement or gene therapies, based on the molecular and genetic characteristics of each patient. Moreover, conducting longitudinal studies in patients with Desbuquois dysplasia would provide valuable data on disease progression, response to treatment, and long-term outcomes, helping to identify critical periods for intervention that might improve patient outcomes. Finally, the development and implementation of advanced molecular diagnostic techniques could facilitate an earlier and more accurate diagnosis of Desbuquois dysplasia, allowing for early intervention and potentially improving the quality of life and prognosis in affected individuals. While significant progress has been made in understanding Desbuquois dysplasia, ongoing research is essential to translate these findings into improved clinical care.

[4] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.396) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[5] High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

Authors: R. Brommage, C. Ohlsson
Year: 2020
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/3b9e1d0da086028d9f89e99a06b7222353ab6b2d
DOI: 10.3389/fendo.2019.00934
PMID: 32117046
PMCID: 7010808
Citations: 25
Influential citations: 1
Summary: Data is organized for 441 human genetic bone disorders with regard to heredity, gene function, molecular pathways, and fidelity of relevant mouse models to mimic the human skeletal disorders to identify mutant genes responsible for human rare genetic skeletal disorders.
Evidence snippets:
Snippet 1 (score: 0.391) > Rare human genetic diseases cumulatively affect about 1 in 200 individuals and involve an estimated 7,000 genes. Major research efforts are underway to identify these mutant genes and characterize their disease phenotypes. Knowledge gained can guide therapies and provide hypotheses to develop future treatments. As recently summarized (1), "Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing." > Rare human genetic skeletal dysplasias affect about 1 in 5,000 individuals (2) and account for 5% of all birth defects (3). The International Skeletal Dysplasia Society (ISDS, https://www.isds. ch), promotes scientific progress in the field of skeletal dysplasias and dysostoses, meets every second year, and published skeletal nosology summaries during 2001 (4), 2006 (5), 2010 (6), 2015 (7), and 2019 (8). There are presently 441 skeletal nosology genes, with an average of 20 new genes identified yearly (Figure 1). The classification aims to (i) identify metabolic pathways active in cartilage and bone, and their regulatory mechanisms; (ii) identify cellular signaling networks and gene expression sequences implicated in skeletal development; (iii) identify candidate genes for genetic disorders; (iv) facilitate integration of data coming from spontaneous and genetically engineered mouse mutants; (v) help in developing diagnostic strategies; (vi) stimulate the design and exploration of new therapeutic possibilities; and (vii) provide a knowledge framework accessible to physicians as well as to basic scientists and thus to facilitate communication between clinical genetics and pediatrics and the basic sciences (4). > The objectives of the present review include further characterizations of these 441 skeletal nosology genes and evaluating the reliability of mutant mouse models to mimic these human skeletal disorders.

[6] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
Year: 2021
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
DOI: 10.1002/mgg3.1809
PMID: 34519438
PMCID: 8580094
Citations: 12
Influential citations: 2
Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
Evidence snippets:
Snippet 1 (score: 0.390) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[7] Therapies for Mitochondrial Disease: Past, Present, and Future

Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
Year: 2025
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
DOI: 10.1002/jimd.70065
PMID: 40714961
PMCID: 12301291
Citations: 2
Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
Evidence snippets:
Snippet 1 (score: 0.388) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[8] WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

Authors: Yentl Huybrechts, G. Mortier, E. Boudin, W. Van Hul
Year: 2020
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/00fd0aa090f258a34c6590bc3dee4b211ecb0929
DOI: 10.3389/fendo.2020.00165
PMID: 32328030
PMCID: 7160326
Citations: 95
Summary: This review discusses the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the Wingless and int-1 (WNT) signaling pathway.
Evidence snippets:
Snippet 1 (score: 0.387) > The identification of novel disease-causing genes for rare skeletal dysplasias accelerated significantly in the last decades, initially by positional cloning efforts and more recently by the availability of next-generation sequencing technology. This resulted in the identification of the disease-causing gene for 92% of the skeletal disorders (6). The increased knowledge on monogenic diseases resulted in a better understanding of the pathological mechanisms and highlighted which pathways regulate specific cellular processes. This information is also relevant for understanding more common multifactorial diseases. Furthermore, it has been shown that therapeutic targets which are based on genetic evidence from Mendelian traits as well as genome-wide association studies (GWASs) are more likely to be successful in clinical studies for multifactorial diseases (150). Here, we focused on skeletal dysplasias caused by mutations in genes that encode proteins that are directly involved in one of the WNT signaling pathways. As shown in Table 1, mutations in these genes can result in a variety of skeletal dysplasias, each with specific clinical features. The broad spectrum of clinical observations reflect the cellular and spatial functions of WNT signaling, some of them associated with embryonal development, others with bone mass and homeostasis in adult life. For example, the clinical features of RS and OMOD are similar which led to the hypothesis that all causative genes are involved in the WNT/PCP pathway which is previously shown to be important during limb development (Figure 2) (102). On the other hand, the influence of canonical WNT signaling on bone mass was highlighted by unraveling the underlying pathogenic mechanisms of disorders with a progressively increasing bone mass such as sclerosteosis, Van Buchem disease, and high bone mass phenotypes (osteosclerosis) (51,53,57,107,113). The genes causing these disorders, SOST, LRP4, LRP5, and LRP6, are all involved in the canonical WNT signaling pathway (Figure 3), and all mutations reported result in an increased canonical WNT signaling (Table 1).

[9] Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

Authors: Alessandra Guasto, V. Cormier-Daire
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/c5466b45e1a7e5aa8e7ad05c7d9287a9e84e9262
DOI: 10.3390/ijms22094321
PMID: 33919228
PMCID: 8122623
Citations: 51
Summary: The principal signaling pathways involved in bone development and their associated skeletal dysplasia are reviewed and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis.
Evidence snippets:
Snippet 1 (score: 0.385) > In this review, we discussed the main signaling pathways involved in bone development and how mutations in their components have been associated with SD. It is important to highlight that even if the signaling pathways have been discussed independently, there is a complex cross-talk among them at multiple levels. This, in association with the evidence that the mutation consequences depend on the specificity of the mutations and on their temporal and spatial mode of action, makes more difficult the understanding of the physiopathological mechanisms of these diseases. Moreover, these signaling pathways can be secondarily affected by alterations in other cellular processes, such as extracellular matrix regulation or metabolic processing. Indeed, several skeletal dysplasia, that we decided to omit in this review, have been associated with mutations in these processes. Fortunately, in the last decade, the development of new technologies, like whole exome and genome sequencing has accelerated the identification of skeletal dysplasia-causing mutations. On the other hand, the development of CRISPR-Cas9 technology and of several mouse models is helping the deciphering of the physiopathological mechanisms. Advanced genetic testing is also helping the diagnosis of skeletal dysplasia. The diagnosis and management of these pathologies have long been based on clinical feature and skeletal imaging. Today, these key techniques are increasingly combined with the genetic testing in order to obtain a more accurate and early diagnosis of SD. It also aids in prognosis and in counselling families regarding genetic recurrence risk and preconceptional reproductive planning [212][213][214]. These continuous discoveries will help to expand the genotype-phenotype correlation of SD and to develop new therapeutic strategies. Nowadays, few treatments are available for SD, but several clinical trials are ongoing to validate new drugs targeting specifically these pathways in achondroplasia or FOP for example, and highlighting the importance of multidisciplinary cross talks (from bed to bench side) [215].

[10] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
Year: 2021
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
DOI: 10.3389/fendo.2021.709711
PMID: 34539568
PMCID: 8444146
Citations: 21
Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
Evidence snippets:
Snippet 1 (score: 0.383) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[11] Role of Transcriptomics in Precision Oncology

Authors: Ruby Srivastava
Year: 2024
Venue: Reports of Radiotherapy and Oncology
URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
DOI: 10.5812/rro-142195
Citations: 4
Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
Evidence snippets:
Snippet 1 (score: 0.377) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.375) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[13] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
Year: 2025
Venue: Signal Transduction and Targeted Therapy
URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
DOI: 10.1038/s41392-025-02179-x
PMID: 40328798
PMCID: 12056177
Citations: 32
Influential citations: 1
Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
Evidence snippets:
Snippet 1 (score: 0.372) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

Authors: Hao Xiong, Jinsheng Guo
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
DOI: 10.3390/ph18040507
PMID: 40283943
PMCID: 12030350
Citations: 7
Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
Evidence snippets:
Snippet 1 (score: 0.372) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

Authors: O. Tsukamoto
Year: 2019
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
DOI: 10.3390/ijms21010226
PMID: 31905684
PMCID: 6982115
Citations: 16
Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
Evidence snippets:
Snippet 1 (score: 0.370) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[16] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.370) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[17] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.369) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[18] The ties that bind: functional clusters in limb-girdle muscular dystrophy

Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
Year: 2020
Venue: Skeletal Muscle
URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
DOI: 10.1186/s13395-020-00240-7
PMID: 32727611
PMCID: 7389686
Citations: 23
Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
Evidence snippets:
Snippet 1 (score: 0.368) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[19] The ties that bind: functional clusters in limb-girdle muscular dystrophy

Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
Year: 2020
Venue: Skeletal Muscle
URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
DOI: 10.1186/s13395-020-00240-7
Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
Evidence snippets:
Snippet 1 (score: 0.368) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

Notes

This provider combines search_papers_by_relevance with snippet_search.
No synthesis or second-stage model call is performed.

Schneckenbecken Dysplasia

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schneckenbecken Dysplasia. Core disease mechanisms, molecular and cellular...

Relevant Papers

[1] EndoCompass Project: Research Roadmap for Calcium and Bone Endocrinology

[2] New therapeutic targets in rare genetic skeletal diseases

[3] Clinical and Genetic Insights into Desbuquois Dysplasia: Review of 111 Case Reports

[4] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

[5] High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

[6] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

[7] Therapies for Mitochondrial Disease: Past, Present, and Future

[8] WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

[9] Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

[10] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

[11] Role of Transcriptomics in Precision Oncology

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

[13] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

[15] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

[16] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

[17] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

[18] The ties that bind: functional clusters in limb-girdle muscular dystrophy

[19] The ties that bind: functional clusters in limb-girdle muscular dystrophy

Notes