👪

Inheritance

1

Autosomal Recessive

Autosomal recessive inheritance. Genetic heterogeneity with mutations in multiple ciliary transport genes.

Show evidence (1 reference)

PMID:24183449 PARTIAL

"Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period."

Confirms autosomal recessive inheritance of SRP type III.

◆

Subtypes

4

Type I (Saldino-Noonan)

The original SRPS subtype described by Saldino and Noonan. Characterized by markedly dysplastic long bones with rounded metaphyses, a narrow thorax due to short ribs, cystic renal dysplasia, cardiovascular defects, pancreatic cysts, and abnormal genitalia. Polydactyly is variably present. Death occurs in the perinatal period from pulmonary hypoplasia.

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."

Confirms the four-type classification of SRPS including Type I Saldino-Noonan.

Type II (Majewski)

Caused by biallelic mutations in NEK1. Characterized by disproportionately short tibiae, preaxial and postaxial polydactyly, cleft lip and palate, and genital anomalies. Hypoplastic lungs cause perinatal death.

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"Affected individuals had a narrow thorax, hypoplastic lungs, polysyndactyly, disproportionate dwarfism, and cleft lip and palate."

Describes the cardinal clinical features of Majewski-type SRPS in the context of NEK1 mutations.

Type III (Verma-Naumoff)

The most extensively characterized subtype, caused by mutations in DYNC2H1, WDR34, or IFT80. Considered part of a spectrum with Jeune ATD. Characterized by short ribs, narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations including renal cystic disease. Lethal in the perinatal period.

Show evidence (1 reference)

PMID:24183449 SUPPORT Human Clinical

"Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period."

Defines SRP Type III with its cardinal clinical features and perinatal lethality.

Type IV (Beemer-Langer)

Clinically distinct from Types I–III; polydactyly is typically absent. Characterized by a narrow thorax, short limbs, brain anomalies including agenesis of corpus callosum, and internal organ malformations. The molecular basis overlaps with dynein-2 complex and IFT gene mutations.

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."

Confirms existence of four distinct SRPS subtypes including Type IV Beemer-Langer.

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Pathophysiology

2

Intraflagellar Transport and Ciliogenesis Defects

SRPS are caused by mutations in genes encoding components of the intraflagellar transport (IFT) machinery, dynein motor complexes, and basal body proteins. These mutations disrupt primary cilium assembly and maintenance, producing structurally abnormal cilia (shortened, bulbous tips) or reduced cilia number.

Intraflagellar Transport GO:0042073 Cilium Assembly GO:0060271

Primary Cilium GO:0005929

Downstream

Hedgehog Signaling Disruption in Skeletal Development

Renal Cystic Disease

Congenital Hepatic Fibrosis

Cardiovascular Defects

Cleft Palate

Cleft Upper Lip

Renal Hypoplasia

Polyhydramnios

Show evidence (4 references)

PMID:22791528 SUPPORT

"10 different genes have been identified as responsible for seven "skeletal" ciliopathies. Mutations have been identified in dynein motor (DYNC2H1), in intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19, and TTC21B) as well as in genes responsible for the basal body..."

Comprehensive overview showing mutations across dynein, IFT, and basal body genes.

PMID:21211617 SUPPORT

"absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo"

Demonstrates that NEK1 loss-of-function directly impairs ciliogenesis.

PMID:24183449 SUPPORT

"primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip"

Shows direct ciliary structural abnormalities in WDR34-mutant cells.

+ 1 more reference

Hedgehog Signaling Disruption in Skeletal Development

Primary cilia are essential for transduction of Hedgehog signaling, which is critical for endochondral ossification and limb patterning. Ciliary dysfunction from IFT/dynein defects disrupts Hedgehog-dependent chondrocyte proliferation and differentiation, leading to severe skeletal shortening and polydactyly. The skeletal and organ phenotypes in SRPS are more severe than in Jeune syndrome, reflecting a greater degree of ciliary dysfunction.

Chondrocyte CL:0000138

Hedgehog Signaling GO:0007224

Downstream

Extremely Short Ribs

Narrow Thorax

Polydactyly

Severe Limb Shortening

Respiratory Insufficiency and Pulmonary Hypoplasia

Micromelia

Short Foot

Abnormal Metaphysis Morphology

Respiratory Insufficiency

Short Thorax

Postaxial Hand Polydactyly

Absent or Minimally Ossified Vertebral Bodies

Show evidence (1 reference)

PMID:22791528 PARTIAL

"primary cilia play a vital role in transduction of signals in the hedgehog pathway that is especially important in skeletal development"

Establishes the role of primary cilia and hedgehog signaling in skeletal ciliopathies.

⬡

Pathograph

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

●

Phenotypes

20

Cardiovascular 1

Cardiovascular Defects Abnormal heart morphology HP:0001627

Digestive 1

Congenital Hepatic Fibrosis Hepatic fibrosis HP:0001395

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"characterized by a narrow thorax due to short ribs, cleft lip, and/or cleft palate, cystic renal dysplasia, congenital hepatic fibrosis, pancreatic cysts, ocular and cerebral anomalies, as well as abnormal genitalia"

Lists congenital hepatic fibrosis as a characteristic feature of SRPS across subtypes.

Genitourinary 1

Renal Cystic Disease Renal cyst HP:0000107

Show evidence (1 reference)

PMID:24183449 NO_EVIDENCE

"numerous extraskeletal malformations"

Renal cystic disease is among the extraskeletal malformations in SRP.

Head and Neck 1

Cleft Palate Cleft palate HP:0000175

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"characterized by a narrow thorax due to short ribs, cleft lip, and/or cleft palate, cystic renal dysplasia, congenital hepatic fibrosis, pancreatic cysts, ocular and cerebral anomalies, as well as abnormal genitalia"

Documents cleft lip and/or palate as a characteristic craniofacial feature in SRPS.

Limbs 6

Polydactyly Polydactyly HP:0010442

Show evidence (1 reference)

PMID:19442771 PARTIAL

"short ribs and a narrow thorax, short long bones, inconstant polydactyly"

Polydactyly is a variable but recognized feature in the ATD-SRP spectrum.

Severe Limb Shortening Limb undergrowth HP:0009826

Show evidence (1 reference)

PMID:24183449 SUPPORT

"characterized by short ribs, a narrow thorax, short long bones"

Short long bones are part of the defining phenotype.

Micromelia VERY_FREQUENT Micromelia HP:0002983

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0002983 | Micromelia | Very frequent (99-80%)"

Orphanet lists micromelia as a very frequent feature of SRPS Verma-Naumoff type.

Short Foot VERY_FREQUENT Short foot HP:0001773

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0001773 | Short foot | Very frequent (99-80%)"

Orphanet lists short foot as a very frequent feature of SRPS Verma-Naumoff type.

Abnormal Metaphysis Morphology VERY_FREQUENT Abnormal metaphysis morphology HP:0000944

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0000944 | Abnormal metaphysis morphology | Very frequent (99-80%)"

Orphanet lists abnormal metaphysis morphology as a very frequent feature of SRPS Verma-Naumoff type.

Postaxial Hand Polydactyly FREQUENT Postaxial hand polydactyly HP:0001162

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0001162 | Postaxial hand polydactyly | Frequent (79-30%)"

Orphanet lists postaxial hand polydactyly as a frequent feature of SRPS Verma-Naumoff type.

Musculoskeletal 2

Extremely Short Ribs Short ribs HP:0000773

Show evidence (2 references)

PMID:24183449 SUPPORT

"characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period"

Describes the cardinal skeletal features of SRP type III including short ribs and perinatal lethality.

PMID:19442771 PARTIAL

"Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof"

Confirms short ribs as characteristic of the ATD-SRP spectrum.

Narrow Thorax Narrow chest HP:0000774

Show evidence (1 reference)

PMID:24183449 SUPPORT

"characterized by short ribs, a narrow thorax, short long bones"

Narrow thorax is a defining feature of SRP type III.

Prenatal and Birth 1

Polyhydramnios Polyhydramnios HP:0001561

Respiratory 2

Respiratory Insufficiency and Pulmonary Hypoplasia Respiratory insufficiency HP:0002093

Show evidence (2 references)

PMID:25313840 SUPPORT Human Clinical

"The affected child died in the neonatal period due to pulmonary hypoplasia leading to respiratory insufficiency"

Directly documents perinatal death from pulmonary hypoplasia and respiratory insufficiency in a newborn with short-rib syndrome.

PMID:24183449 SUPPORT Human Clinical

"lethal in the perinatal period"

Perinatal lethality due to respiratory failure is a defining feature across SRPS subtypes.

Respiratory Insufficiency VERY_FREQUENT Respiratory insufficiency HP:0002093

Show evidence (2 references)

ORPHA:93271 SUPPORT Human Clinical

"HP:0002093 | Respiratory insufficiency | Very frequent (99-80%)"

Orphanet lists respiratory insufficiency as a very frequent feature of SRPS Verma-Naumoff type.

PMID:24183449 SUPPORT Human Clinical

"numerous extraskeletal malformations and is lethal in the perinatal period"

Confirms that the extreme thoracic restriction in SRPS type III leads to lethal respiratory compromise in the perinatal period.

Other 5

Short Thorax VERY_FREQUENT Short thorax HP:0010306

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0010306 | Short thorax | Very frequent (99-80%)"

Orphanet lists short thorax as a very frequent feature of SRPS Verma-Naumoff type.

Absent or Minimally Ossified Vertebral Bodies FREQUENT Absent or minimally ossified vertebral bodies HP:0004599

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0004599 | Absent or minimally ossified vertebral bodies | Frequent (79-30%)"

Orphanet lists absent or minimally ossified vertebral bodies as a frequent feature of SRPS Verma-Naumoff type.

Renal Hypoplasia FREQUENT Renal hypoplasia HP:0000089

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0000089 | Renal hypoplasia | Frequent (79-30%)"

Orphanet lists renal hypoplasia as a frequent feature of SRPS Verma-Naumoff type.

Congenital Hepatic Fibrosis FREQUENT Congenital hepatic fibrosis HP:0002612

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0002612 | Congenital hepatic fibrosis | Frequent (79-30%)"

Orphanet lists congenital hepatic fibrosis as a frequent feature of SRPS Verma-Naumoff type.

Cleft Upper Lip FREQUENT Cleft upper lip HP:0000204

Show evidence (1 reference)

ORPHA:93271 SUPPORT Human Clinical

"HP:0000204 | Cleft upper lip | Frequent (79-30%)"

Orphanet lists cleft upper lip as a frequent feature of SRPS Verma-Naumoff type.

🧬

Genetic Associations

4

DYNC2H1 Mutations (SRP Type III/Verma-Naumoff) (Causative)

Show evidence (2 references)

PMID:19442771 PARTIAL

"we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group"

Landmark paper establishing that DYNC2H1 mutations cause both ATD and SRP type III, proving they are a single spectrum.

PMID:19442771 SUPPORT

"identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families"

Identifies DYNC2H1 mutations in both homozygous and compound heterozygous states.

NEK1 Mutations (SRP Type II/Majewski) (Causative)

Show evidence (3 references)

PMID:21211617 SUPPORT

"We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia"

Discovery paper identifying NEK1 as the cause of SRP Majewski type.

PMID:21211617 SUPPORT

"NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis"

Characterizes NEK1 function including its role in ciliogenesis.

PMID:21211617 PARTIAL

"We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family"

Reports digenic inheritance involving NEK1 and DYNC2H1, suggesting oligogenic complexity.

WDR34 Mutations (SRP Type III) (Causative)

Show evidence (2 references)

PMID:24183449 SUPPORT

"homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family"

Identifies WDR34 mutations in multiple SRP type III families.

PMID:24183449 SUPPORT

"This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies"

Reveals unexpected link between NF-kappaB signaling and ciliary function in SRP.

IFT80 Mutations (Causative)

Show evidence (2 references)

PMID:19648123 SUPPORT

"mutations in IFT80 can also be responsible for a lethal form of SRP and provide the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum"

Demonstrates that IFT80 mutations can cause both lethal SRP and milder JATD, establishing the Jeune-Verma-Naumoff spectrum.

PMID:19648123 SUPPORT

"Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion in exon 8 (G241R) in only one SRP case closely related to the type III phenotype"

Identifies specific IFT80 mutation in an SRP type III case.

💊

Medical Actions

2

Perinatal Palliative Care

Action: supportive care MAXO:0000950

SRPS is uniformly lethal in the perinatal period due to pulmonary hypoplasia. Management is directed toward comfort care and family support. Advance care planning, goals-of-care discussions with parents, neonatal palliative care, and bereavement support are integral to management. Mechanical ventilation does not alter the lethal outcome and is rarely attempted outside of diagnostic uncertainty contexts.

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"The affected child died in the neonatal period due to pulmonary hypoplasia leading to respiratory insufficiency"

Documents perinatal death from pulmonary hypoplasia in SRPS, establishing that management is palliative.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling is essential for all families with an affected infant given the autosomal recessive inheritance (25% recurrence risk). Counseling encompasses explanation of the causative gene variant and inheritance pattern, recurrence risk quantification, reproductive options including prenatal diagnosis and preimplantation genetic diagnosis, and psychosocial support for grief and bereavement. Cascade testing of at-risk family members is indicated.

Show evidence (1 reference)

PMID:25313840 SUPPORT Human Clinical

"it is essential to establish the correct diagnosis in order to facilitate adequate genetic counseling and to alert the families of other possible affected members that could benefit from earlier intervention"

Supports the importance of genetic counseling for SRPS-affected families to enable recurrence risk assessment and cascade family evaluation.

{ }

Source YAML

click to show

name: Short-Rib Polydactyly Syndrome
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
description: >
  Short-rib polydactyly syndromes (SRPS) are a group of autosomal recessive lethal
  skeletal ciliopathies characterized by extremely short ribs, narrow thorax,
  short limbs, polydactyly (variably present), and multiorgan abnormalities. They
  represent the severe end of the short-rib thoracic dysplasia spectrum, with Jeune
  syndrome at the milder end. Four classical subtypes are recognized: Type I
  (Saldino-Noonan), Type II (Majewski), Type III (Verma-Naumoff), and Type IV
  (Beemer-Langer), all caused by mutations in genes encoding components of the
  intraflagellar transport machinery, dynein motor complexes, or related ciliogenesis
  factors. Death typically occurs in the perinatal period from pulmonary hypoplasia
  and respiratory insufficiency.
disease_term:
  preferred_term: Short rib-polydactyly syndrome
  term:
    id: MONDO:0015461
    label: short rib-polydactyly syndrome
parents:
- Ciliopathies
- Short-Rib Dysplasias
has_subtypes:
- name: Type I
  display_name: "Type I (Saldino-Noonan)"
  description: >-
    The original SRPS subtype described by Saldino and Noonan. Characterized by
    markedly dysplastic long bones with rounded metaphyses, a narrow thorax due to
    short ribs, cystic renal dysplasia, cardiovascular defects, pancreatic cysts,
    and abnormal genitalia. Polydactyly is variably present. Death occurs in the
    perinatal period from pulmonary hypoplasia.
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."
    explanation: Confirms the four-type classification of SRPS including Type I Saldino-Noonan.
- name: Type II
  display_name: "Type II (Majewski)"
  description: >-
    Caused by biallelic mutations in NEK1. Characterized by disproportionately
    short tibiae, preaxial and postaxial polydactyly, cleft lip and palate, and
    genital anomalies. Hypoplastic lungs cause perinatal death.
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals had a narrow thorax, hypoplastic lungs, polysyndactyly, disproportionate dwarfism, and cleft lip and palate."
    explanation: Describes the cardinal clinical features of Majewski-type SRPS in the context of NEK1 mutations.
- name: Type III
  display_name: "Type III (Verma-Naumoff)"
  description: >-
    The most extensively characterized subtype, caused by mutations in DYNC2H1,
    WDR34, or IFT80. Considered part of a spectrum with Jeune ATD. Characterized
    by short ribs, narrow thorax, short long bones, an abnormal acetabulum, and
    numerous extraskeletal malformations including renal cystic disease. Lethal in
    the perinatal period.
  evidence:
  - reference: PMID:24183449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period."
    explanation: Defines SRP Type III with its cardinal clinical features and perinatal lethality.
- name: Type IV
  display_name: "Type IV (Beemer-Langer)"
  description: >-
    Clinically distinct from Types I–III; polydactyly is typically absent.
    Characterized by a narrow thorax, short limbs, brain anomalies including
    agenesis of corpus callosum, and internal organ malformations. The molecular
    basis overlaps with dynein-2 complex and IFT gene mutations.
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."
    explanation: Confirms existence of four distinct SRPS subtypes including Type IV Beemer-Langer.
inheritance:
- name: Autosomal Recessive
  description: >
    Autosomal recessive inheritance. Genetic heterogeneity with mutations
    in multiple ciliary transport genes.
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: PARTIAL
    snippet: >-
      Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an
      autosomal-recessive chondrodysplasia characterized by short ribs, a narrow
      thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal
      malformations and is lethal in the perinatal period.
    explanation: "Confirms autosomal recessive inheritance of SRP type III."
prevalence:
- population: Published literature worldwide
  prevalence_class: ULTRA_RARE
  percentage: Extremely rare; precise population prevalence not established
  notes: >-
    PMID-indexed literature consistently describes classic short-rib
    polydactyly syndromes as lethal perinatal skeletal ciliopathies reported in
    small family and fetal series rather than robust population registries.
  evidence:
  - reference: PMID:24183449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period."
    explanation: This human genetics report confirms the syndrome's perinatal lethality and extreme rarity in clinical series.
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."
    explanation: This pathology review supports that the classic SRPS entities are rare lethal osteochondrodysplasias rather than common, registry-defined disorders.
pathophysiology:
- name: Intraflagellar Transport and Ciliogenesis Defects
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >
    SRPS are caused by mutations in genes encoding components of the
    intraflagellar transport (IFT) machinery, dynein motor complexes,
    and basal body proteins. These mutations disrupt primary cilium
    assembly and maintenance, producing structurally abnormal cilia
    (shortened, bulbous tips) or reduced cilia number.
  biological_processes:
  - preferred_term: Intraflagellar Transport
    term:
      id: GO:0042073
      label: intraciliary transport
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:22791528
    reference_title: "Ciliary disorder of the skeleton."
    supports: SUPPORT
    snippet: >-
      10 different genes have been identified as responsible for seven "skeletal"
      ciliopathies. Mutations have been identified in dynein motor (DYNC2H1), in
      intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19,
      and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and
      EVC2)
    explanation: "Comprehensive overview showing mutations across dynein, IFT, and basal body genes."
  - reference: PMID:21211617
    reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
    supports: SUPPORT
    snippet: >-
      absence of functional full-length NEK1 severely reduces cilia number and
      alters ciliar morphology in vivo
    explanation: "Demonstrates that NEK1 loss-of-function directly impairs ciliogenesis."
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      primary cilia in WDR34 mutant fibroblasts were significantly shorter than
      normal and had a bulbous tip
    explanation: "Shows direct ciliary structural abnormalities in WDR34-mutant cells."
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      DYNC2H1 is a component of a cytoplasmic dynein complex and is directly
      involved in the generation and maintenance of cilia
    explanation: "Confirms DYNC2H1 role in ciliary generation and maintenance."
  downstream:
  - target: Hedgehog Signaling Disruption in Skeletal Development
  - target: Renal Cystic Disease
  - target: Congenital Hepatic Fibrosis
  - target: Cardiovascular Defects
  - target: Cleft Palate
  - target: Cleft Upper Lip
  - target: Renal Hypoplasia
  - target: Polyhydramnios
- name: Hedgehog Signaling Disruption in Skeletal Development
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >
    Primary cilia are essential for transduction of Hedgehog signaling,
    which is critical for endochondral ossification and limb patterning.
    Ciliary dysfunction from IFT/dynein defects disrupts Hedgehog-dependent
    chondrocyte proliferation and differentiation, leading to severe skeletal
    shortening and polydactyly. The skeletal and organ phenotypes in SRPS
    are more severe than in Jeune syndrome, reflecting a greater degree of
    ciliary dysfunction.
  biological_processes:
  - preferred_term: Hedgehog Signaling
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:22791528
    reference_title: "Ciliary disorder of the skeleton."
    supports: PARTIAL
    snippet: >-
      primary cilia play a vital role in transduction of signals in the hedgehog
      pathway that is especially important in skeletal development
    explanation: "Establishes the role of primary cilia and hedgehog signaling in skeletal ciliopathies."
  downstream:
  - target: Extremely Short Ribs
  - target: Narrow Thorax
  - target: Polydactyly
  - target: Severe Limb Shortening
  - target: Respiratory Insufficiency and Pulmonary Hypoplasia
  - target: Micromelia
  - target: Short Foot
  - target: Abnormal Metaphysis Morphology
  - target: Respiratory Insufficiency
  - target: Short Thorax
  - target: Postaxial Hand Polydactyly
  - target: Absent or Minimally Ossified Vertebral Bodies
phenotypes:
- name: Extremely Short Ribs
  description: >
    Severely shortened ribs leading to a markedly constricted thorax.
    More severe than in Jeune syndrome, causing perinatal lethality.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      characterized by short ribs, a narrow thorax, short long bones, an abnormal
      acetabulum, and numerous extraskeletal malformations and is lethal in the
      perinatal period
    explanation: "Describes the cardinal skeletal features of SRP type III including short ribs and perinatal lethality."
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: PARTIAL
    snippet: >-
      Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive
      chondrodysplasia characterized by short ribs and a narrow thorax, short long
      bones, inconstant polydactyly, and trident acetabular roof
    explanation: "Confirms short ribs as characteristic of the ATD-SRP spectrum."
- name: Narrow Thorax
  description: >
    Extremely narrow thoracic cage incompatible with postnatal
    respiratory function.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      characterized by short ribs, a narrow thorax, short long bones
    explanation: "Narrow thorax is a defining feature of SRP type III."
- name: Polydactyly
  description: >
    Polydactyly, typically postaxial, is a cardinal feature present
    in most SRPS subtypes. In Type II (Majewski), both preaxial and postaxial
    polydactyly occur. Polydactyly is typically absent in Type IV (Beemer-Langer).
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: PARTIAL
    snippet: >-
      short ribs and a narrow thorax, short long bones, inconstant polydactyly
    explanation: "Polydactyly is a variable but recognized feature in the ATD-SRP spectrum."
- name: Severe Limb Shortening
  description: >
    Severe shortening of long bones (micromelia) more pronounced
    than in Jeune syndrome.
  phenotype_term:
    preferred_term: Limb undergrowth
    term:
      id: HP:0009826
      label: Limb undergrowth
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      characterized by short ribs, a narrow thorax, short long bones
    explanation: "Short long bones are part of the defining phenotype."
- name: Respiratory Insufficiency and Pulmonary Hypoplasia
  description: >
    Pulmonary hypoplasia due to thoracic constriction leads to respiratory
    insufficiency and death in the perinatal period. This is the primary cause
    of death in SRPS across all subtypes. Unlike Jeune ATD, there is insufficient
    lung development for postnatal respiratory survival.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected child died in the neonatal period due to pulmonary hypoplasia leading to respiratory insufficiency"
    explanation: >-
      Directly documents perinatal death from pulmonary hypoplasia and respiratory
      insufficiency in a newborn with short-rib syndrome.
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lethal in the perinatal period"
    explanation: "Perinatal lethality due to respiratory failure is a defining feature across SRPS subtypes."
- name: Renal Cystic Disease
  description: >
    Renal cystic dysplasia as part of the multiorgan ciliopathy
    phenotype.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: NO_EVIDENCE
    snippet: >-
      numerous extraskeletal malformations
    explanation: "Renal cystic disease is among the extraskeletal malformations in SRP."
- name: Congenital Hepatic Fibrosis
  description: >
    Congenital hepatic fibrosis is a recognized visceral manifestation in SRPS,
    reflecting the shared ciliopathy mechanisms affecting biliary ductal
    morphogenesis. The hepatic pathology is histologically indistinguishable
    from that in other ciliopathic conditions such as Meckel and Joubert syndromes.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by a narrow thorax due to short ribs, cleft lip, and/or cleft palate, cystic renal dysplasia, congenital hepatic fibrosis, pancreatic cysts, ocular and cerebral anomalies, as well as abnormal genitalia"
    explanation: Lists congenital hepatic fibrosis as a characteristic feature of SRPS across subtypes.
- name: Cleft Palate
  description: >
    Cleft lip and/or palate is a recognized craniofacial malformation in SRPS,
    particularly prominent in Type II (Majewski) where it is a characteristic
    feature, and also described in Type I (Saldino-Noonan). Oral clefts
    reflect ciliopathic disruption of palatal and midface development.
  subtypes:
  - Type I
  - Type II
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by a narrow thorax due to short ribs, cleft lip, and/or cleft palate, cystic renal dysplasia, congenital hepatic fibrosis, pancreatic cysts, ocular and cerebral anomalies, as well as abnormal genitalia"
    explanation: Documents cleft lip and/or palate as a characteristic craniofacial feature in SRPS.
- name: Cardiovascular Defects
  description: >
    Congenital heart defects including transposition of great vessels,
    atrioventricular canal defects, and other structural anomalies.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
- name: Polyhydramnios
  description: >
    Polyhydramnios is frequently observed prenatally due to restricted fetal
    swallowing and may be the first clinical clue prompting fetal imaging.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
- category: Skeletal
  name: Micromelia
  description: >
    Severe shortening of all long bones (micromelia) is a very frequent
    skeletal feature in the Verma-Naumoff type of short-rib polydactyly syndrome.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002983 | Micromelia | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists micromelia as a very frequent feature of SRPS Verma-Naumoff type.
- category: Skeletal
  name: Short Foot
  description: >
    Short feet are a very frequent feature of SRPS, reflecting global shortening
    of tubular bones of the lower extremities.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001773 | Short foot | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists short foot as a very frequent feature of SRPS Verma-Naumoff type.
- category: Skeletal
  name: Abnormal Metaphysis Morphology
  description: >
    The metaphyses of tubular bones show characteristic abnormalities in SRPS
    Verma-Naumoff type, including round metaphyseal ends and lateral spikes.
  phenotype_term:
    preferred_term: Abnormal metaphysis morphology
    term:
      id: HP:0000944
      label: Abnormal metaphysis morphology
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000944 | Abnormal metaphysis morphology | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists abnormal metaphysis morphology as a very frequent feature
      of SRPS Verma-Naumoff type.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >
    Lethal respiratory insufficiency results from the extremely narrow thorax
    and pulmonary hypoplasia, causing death in the perinatal period.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002093 | Respiratory insufficiency | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists respiratory insufficiency as a very frequent feature of
      SRPS Verma-Naumoff type.
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      numerous extraskeletal malformations and is lethal in the perinatal period
    explanation: >-
      Confirms that the extreme thoracic restriction in SRPS type III leads to
      lethal respiratory compromise in the perinatal period.
- category: Skeletal
  name: Short Thorax
  description: >
    The thorax is severely shortened as well as narrowed in SRPS Verma-Naumoff
    type, contributing to the lethal pulmonary restriction.
  phenotype_term:
    preferred_term: Short thorax
    term:
      id: HP:0010306
      label: Short thorax
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0010306 | Short thorax | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists short thorax as a very frequent feature of SRPS Verma-Naumoff type.
- category: Skeletal
  name: Postaxial Hand Polydactyly
  description: >
    Postaxial (ulnar-side) polydactyly of the hands is the most common form of
    polydactyly in the SRPS Verma-Naumoff spectrum.
  phenotype_term:
    preferred_term: Postaxial hand polydactyly
    term:
      id: HP:0001162
      label: Postaxial hand polydactyly
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001162 | Postaxial hand polydactyly | Frequent (79-30%)"
    explanation: >-
      Orphanet lists postaxial hand polydactyly as a frequent feature of SRPS
      Verma-Naumoff type.
- category: Skeletal
  name: Absent or Minimally Ossified Vertebral Bodies
  description: >
    Vertebral body ossification is severely reduced or absent in SRPS
    Verma-Naumoff type, as part of the global skeletal mineralization defect.
  phenotype_term:
    preferred_term: Absent or minimally ossified vertebral bodies
    term:
      id: HP:0004599
      label: Absent or minimally ossified vertebral bodies
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0004599 | Absent or minimally ossified vertebral bodies | Frequent (79-30%)"
    explanation: >-
      Orphanet lists absent or minimally ossified vertebral bodies as a frequent
      feature of SRPS Verma-Naumoff type.
- category: Renal
  name: Renal Hypoplasia
  description: >
    Renal hypoplasia, distinct from renal cysts, is a frequent manifestation
    of the multisystem ciliopathy in SRPS Verma-Naumoff type.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000089 | Renal hypoplasia | Frequent (79-30%)"
    explanation: >-
      Orphanet lists renal hypoplasia as a frequent feature of SRPS Verma-Naumoff type.
- category: Visceral
  name: Congenital Hepatic Fibrosis
  description: >
    Hepatic fibrosis can occur as part of the visceral ciliopathy phenotype in
    SRPS, reflecting abnormal ductal plate remodeling.
  phenotype_term:
    preferred_term: Congenital hepatic fibrosis
    term:
      id: HP:0002612
      label: Congenital hepatic fibrosis
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002612 | Congenital hepatic fibrosis | Frequent (79-30%)"
    explanation: >-
      Orphanet lists congenital hepatic fibrosis as a frequent feature of SRPS
      Verma-Naumoff type.
- category: Craniofacial
  name: Cleft Upper Lip
  description: >
    Cleft lip, with or without palate, can occur in SRPS as part of the broad
    dysmorphic syndrome. Its presence helps distinguish SRPS from Jeune syndrome.
  phenotype_term:
    preferred_term: Cleft upper lip
    term:
      id: HP:0000204
      label: Cleft upper lip
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:93271
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000204 | Cleft upper lip | Frequent (79-30%)"
    explanation: >-
      Orphanet lists cleft upper lip as a frequent feature of SRPS Verma-Naumoff type.
genetic:
- name: DYNC2H1 Mutations (SRP Type III/Verma-Naumoff)
  subtype: Type III
  association: Causative
  notes: >
    Biallelic mutations in DYNC2H1, the most common cause of both
    JATD and SRP type III. SRP type III (Verma-Naumoff) and JATD
    are now considered variants of a single disorder, with SRP
    representing the severe end.
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: PARTIAL
    snippet: >-
      we conclude that ATD and SRP type III are variants of a single disorder
      belonging to the ciliopathy group
    explanation: "Landmark paper establishing that DYNC2H1 mutations cause both ATD and SRP type III, proving they are a single spectrum."
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1
      (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1
      mutations was also identified in four additional families
    explanation: "Identifies DYNC2H1 mutations in both homozygous and compound heterozygous states."
- name: NEK1 Mutations (SRP Type II/Majewski)
  subtype: Type II
  association: Causative
  notes: >
    Biallelic mutations in NEK1, encoding a kinase involved in
    ciliogenesis. Associated with SRP type II (Majewski type),
    characterized by disproportionately short tibiae and
    preaxial/postaxial polydactyly.
  evidence:
  - reference: PMID:21211617
    reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
    supports: SUPPORT
    snippet: >-
      We used homozygosity mapping in two families with autosomal-recessive short-rib
      polydactyly syndrome Majewski type to identify mutations in NEK1 as an
      underlying cause of this lethal osteochondrodysplasia
    explanation: "Discovery paper identifying NEK1 as the cause of SRP Majewski type."
  - reference: PMID:21211617
    reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
    supports: SUPPORT
    snippet: >-
      NEK1 encodes a serine/threonine kinase with proposed function in DNA
      double-strand repair, neuronal development, and coordination of
      cell-cycle-associated ciliogenesis
    explanation: "Characterizes NEK1 function including its role in ciliogenesis."
  - reference: PMID:21211617
    reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
    supports: PARTIAL
    snippet: >-
      We further substantiate a proposed digenic diallelic inheritance of
      ciliopathies by the identification of heterozygous mutations in NEK1 and
      DYNC2H1 in an additional family
    explanation: "Reports digenic inheritance involving NEK1 and DYNC2H1, suggesting oligogenic complexity."
- name: WDR34 Mutations (SRP Type III)
  subtype: Type III
  association: Causative
  notes: >
    Biallelic mutations in WDR34, encoding a WD repeat protein
    involved in ciliary function and NF-kappaB pathway regulation.
  evidence:
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      homozygosity for three missense mutations in WDR34 were found in three
      independent families, as well as compound heterozygosity for mutations in one
      family
    explanation: "Identifies WDR34 mutations in multiple SRP type III families."
  - reference: PMID:24183449
    reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
    supports: SUPPORT
    snippet: >-
      This report expands on the pathogenesis of SRP type III and demonstrates that a
      regulator of the NF-κB activation pathway is involved in the pathogenesis of the
      skeletal ciliopathies
    explanation: "Reveals unexpected link between NF-kappaB signaling and ciliary function in SRP."
- name: IFT80 Mutations
  subtype: Type III
  association: Causative
  notes: >
    Biallelic mutations in IFT80, a component of the IFT-B complex.
    Can cause both JATD and SRP phenotypes.
  evidence:
  - reference: PMID:19648123
    reference_title: "Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum."
    supports: SUPPORT
    snippet: >-
      mutations in IFT80 can also be responsible for a lethal form of SRP and provide
      the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum
    explanation: "Demonstrates that IFT80 mutations can cause both lethal SRP and milder JATD, establishing the Jeune-Verma-Naumoff spectrum."
  - reference: PMID:19648123
    reference_title: "Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum."
    supports: SUPPORT
    snippet: >-
      Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion
      in exon 8 (G241R) in only one SRP case closely related to the type III phenotype
    explanation: "Identifies specific IFT80 mutation in an SRP type III case."
diagnosis:
- name: Prenatal Diagnosis by Fetal Ultrasound
  description: >-
    SRPS can be identified prenatally by fetal ultrasound, which reveals the
    characteristic narrow thorax, short ribs, shortened long bones, and polydactyly.
    Prenatal diagnosis enables family counseling, delivery planning, and preparation
    for palliative care. Subsequent pregnancies in affected families can be offered
    molecular genetic testing for the familial variant.
  diagnosis_term:
    preferred_term: prenatal ultrasonography
    term:
      id: MAXO:0000072
      label: ultrasonography procedure
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations"
    explanation: >-
      Documents the prenatal expression of SRP type III, supporting the role of
      prenatal diagnosis in affected families.
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    Short-rib polydactyly syndrome is diagnosed prenatally or at birth from the
    severe short-rib/narrow-thorax phenotype with polydactyly and characteristic
    radiographic findings, and is confirmed by molecular genetic testing of the
    skeletal-ciliopathy genes. It is differentiated within the short-rib
    polydactyly group from milder ciliopathies such as Jeune ATD and Ellis-van
    Creveld syndrome; most cases are perinatally lethal.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:22791528
    reference_title: "Ciliary disorder of the skeleton."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the short rib-polydactyly group (SRPs) that includes Verma-Naumoff syndrome (SRP type III), Majewski syndrome (SRP type II), Jeune syndrome (ATD), as well as Ellis-van Creveld syndrome (EVC), the Sensenbrenner syndrome, and, finally, Weyers acrofacial dysostosis."
    explanation: >-
      Defines the short-rib-polydactyly group and its differential diagnosis
      within the skeletal ciliopathies.
  - reference: PMID:22791528
    reference_title: "Ciliary disorder of the skeleton."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations have been identified in dynein motor (DYNC2H1), in intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19, and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and EVC2)."
    explanation: >-
      Supports the panel of skeletal-ciliopathy genes used for molecular
      diagnosis of short-rib polydactyly syndromes.
treatments:
- name: Perinatal Palliative Care
  description: >
    SRPS is uniformly lethal in the perinatal period due to pulmonary hypoplasia.
    Management is directed toward comfort care and family support. Advance care
    planning, goals-of-care discussions with parents, neonatal palliative care,
    and bereavement support are integral to management. Mechanical ventilation
    does not alter the lethal outcome and is rarely attempted outside of diagnostic
    uncertainty contexts.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected child died in the neonatal period due to pulmonary hypoplasia leading to respiratory insufficiency"
    explanation: >-
      Documents perinatal death from pulmonary hypoplasia in SRPS, establishing
      that management is palliative.
- name: Genetic Counseling
  description: >
    Genetic counseling is essential for all families with an affected infant
    given the autosomal recessive inheritance (25% recurrence risk). Counseling
    encompasses explanation of the causative gene variant and inheritance pattern,
    recurrence risk quantification, reproductive options including prenatal
    diagnosis and preimplantation genetic diagnosis, and psychosocial support
    for grief and bereavement. Cascade testing of at-risk family members is
    indicated.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25313840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is essential to establish the correct diagnosis in order to facilitate adequate genetic counseling and to alert the families of other possible affected members that could benefit from earlier intervention"
    explanation: >-
      Supports the importance of genetic counseling for SRPS-affected families
      to enable recurrence risk assessment and cascade family evaluation.
datasets: []

📚

References & Deep Research

Deep Research

2

Disorder ▸

Disorder

Name: Short-Rib Polydactyly Syndrome
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 25

Key Pathophysiology Nodes

Intraflagellar Transport and Ciliogenesis Defects
Hedgehog Signaling Disruption in Skeletal Development
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1101/2020.11.27.400994
DOI:10.1101/2023.06.07.544132
DOI:10.1186/s41065-025-00375-x

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 18 citations 2026-02-10T08:10:38.750151

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Short-Rib Polydactyly Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Short-Rib Polydactyly Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Disease Pathophysiology Research Report: Short-Rib Polydactyly Syndrome (SRPS) / Short-Rib Thoracic Dysplasia (SRTD)

Target Disease - Disease Name: Short-Rib Polydactyly Syndrome (SRPS) / Short-Rib Thoracic Dysplasia (SRTD) - MONDO ID: Not confidently resolved here; SRPS/SRTD are classified within skeletal ciliopathies in current nosology. Please verify MONDO mapping during curation. - Category: Mendelian (autosomal recessive)

Pathophysiology summary Short-Rib Polydactyly Syndrome and the broader SRTD spectrum are skeletal ciliopathies caused by dysfunction of the primary cilium, most often due to variants in intraflagellar transport (IFT) machinery (IFT-A, IFT-B) or the retrograde IFT motor dynein-2. Disrupted ciliary trafficking perturbs Hedgehog (Hh) signaling in limb bud mesenchyme and growth-plate chondrocytes, leading to abnormal skeletal patterning (polydactyly) and chondrodysplasia with thoracic insufficiency, and extends to kidney and retinal phenotypes in overlapping syndromes (e.g., Mainzer–Saldino, Jeune). DYNC2H1 (dynein-2 heavy chain) is a major genetic cause; IFT140/IFT-A defects model short-rib phenotypes with ciliation loss and Hh pathway disruption. Prenatal diagnosis increasingly combines systematic ultrasound with exome sequencing to resolve the high genetic heterogeneity of lethal skeletal dysplasias. (xiong2025anovelcompound pages 8-8, francis2023autonomousandnoncell pages 16-20, getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, francis2023autonomousandnoncell pages 20-24)

1) Core Pathophysiology - Primary mechanisms: Defective intraflagellar transport (anterograde IFT-B and retrograde IFT-A/dynein-2) compromises ciliary structure and signaling competence. In limb and cartilage lineages, this dysregulates Sonic/Ihh signaling required for digit number/patterning and growth-plate proliferation–hypertrophy transitions, producing polydactyly and severe thoracic and long-bone shortening. Kidney tubule and retinal photoreceptor cilia involvement explains cystic kidney disease and retinal degeneration in overlapping phenotypes. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Evidence: “Ift80 and ift172 models… exhibited severe limb deformities, polydactyly… and ciliogenesis defects… implicating cilia-dependent signaling (Hedgehog) in skeletal outcomes.” bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18) - Evidence: Ift140 mutant analyses show “low incidence of ciliation” and “disrupted cilia-transduced Shh signaling” with thoracic dystrophy and polydactyly in mice. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Dysregulated pathways: Hedgehog signaling (Shh in limb bud; Ihh in growth plate) is primary; IFT dysfunction can variably modulate Hh outputs in vivo. Additional contributions from Wnt and cilia-associated microtubule modifications (e.g., tubulin polyglutamylation) are implicated. (getwan2020crisprcas9targetingttc30a pages 16-18) - Affected cellular processes: Ciliogenesis, intraciliary cargo transport (anterograde/retrograde), ciliary maintenance, signal transduction; chondrocyte proliferation/differentiation; epithelial polarity in kidney tubules. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)

2) Key Molecular Players - Genes/Proteins (HGNC): DYNC2H1 (dynein-2 heavy chain), DYNC2LI1, WDR60, WDR34, IFT140, WDR19/IFT144, WDR35/IFT121, TTC21B/IFT139, IFT172, IFT80, IFT52, TRAF3IP1/IFT54, IFT43, IFT22, NEK1. Roles span dynein-2 motor assembly/function and IFT-A/B particle integrity. (getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, xiong2025anovelcompound pages 8-8) - Expert/clinical emphasis: DYNC2H1 is a recurrent cause for SRTD/SRPS; compound heterozygous variants are common in severe prenatal/infantile cases. Front-line genomics (WES/RNA-seq) resolves diverse variant classes. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Quantitative note: DYNC2H1 accounts for a large subset of SRTD3; a 2022 overview notes it “cause[s] SRTD3” and is cited in >50% of such cases in compilations. (markova2022сlinicalandgenetic pages 9-11) - Chemical entities (CHEBI): Not primary etiologic drivers; pathway reference points include Hh morphogens (proteins). Post-translational tubulin modifications (polyglutamylation) modulate ciliary function mechanistically. (getwan2020crisprcas9targetingttc30a pages 16-18) - Cell types (CL): Growth plate chondrocytes; limb bud mesenchymal cells; kidney tubular epithelium; respiratory epithelium; retinal photoreceptors. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Anatomical locations (UBERON): Developing limb/limb bud; thoracic cage/ribs; tracheobronchial tree and lungs; kidney; retina. (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24)

Gene	Complex / Role	Primary Mechanism	GO Biological Processes (examples)	Cellular Component	Primary Tissues / Cell Types	Representative Phenotypes (HPO)	Sources
DYNC2H1	Dynein-2 heavy chain (retrograde IFT motor)	Retrograde IFT failure; impaired ciliary trafficking	Retrograde ciliary transport; intraflagellar transport; Hedgehog signaling pathway	Primary cilium; axoneme	Growth plate chondrocyte; limb bud mesenchyme; respiratory epithelium	Short ribs [HP:0000773]; Narrow thorax [HP:0000774]; Polydactyly [HP:0010442]; Short long bones [HP:0003026]	(xiong2025anovelcompound pages 8-8, markova2022сlinicalandgenetic pages 9-11)
DYNC2LI1	Dynein-2 light/intermediate chain	Dynein-2 assembly/function defect; impaired retrograde IFT	Retrograde ciliary transport; intraflagellar transport	Dynein complex; primary cilium	Growth plate chondrocyte; limb bud mesenchyme	Narrow thorax [HP:0000774]; Polydactyly [HP:0010442]	(markova2022сlinicalandgenetic pages 9-11)
WDR60	Dynein-2 WD-repeat subunit	Dynein motor assembly/cargo binding defects	Protein complex assembly; retrograde ciliary transport	Dynein complex; cilium	Growth plate chondrocyte; limb bud	Short ribs [HP:0000773]; Polydactyly [HP:0010442]	(getwan2020crisprcas9targetingttc30a pages 16-18)
WDR34	Dynein-2 WD-repeat subunit	Dynein assembly / retrograde IFT impairment	Retrograde ciliary transport; intraflagellar transport	Dynein complex; cilium	Growth plate chondrocyte; limb bud	Short long bones [HP:0003026]; Thoracic insufficiency [HP:0004421]	(getwan2020crisprcas9targetingttc30a pages 16-18)
WDR19 / IFT144	IFT-A component (WD-repeat)	Disrupted IFT-A cargo retrieval; altered ciliary signaling	Intraflagellar transport; regulation of signaling	IFT-A complex; ciliary base	Kidney tubular epithelium; retinal photoreceptor; growth plate	Renal cysts [HP:0000107]; Retinal degeneration [HP:0000556]; Narrow thorax [HP:0000774]	(markova2022сlinicalandgenetic pages 9-11)
IFT140	IFT-A core subunit	Loss/reduction of cilia; altered SHH signaling	Intraflagellar transport; Hedgehog signaling pathway	Primary cilium; IFT-A complex	Growth plate chondrocyte; retina; kidney	Thoracic dystrophy; Retinal degeneration [HP:0000556]; Renal cysts [HP:0000107]	(francis2023autonomousandnoncell pages 20-24)
IFT172	IFT-B component	IFT-B destabilization; impaired anterograde transport	Intraflagellar transport; cilium assembly	IFT particle B; axoneme	Limb bud mesenchyme; growth plate	Polydactyly [HP:0010442]; Short long bones [HP:0003026]	(getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 7-9)
IFT80	IFT-B core subunit	Impaired anterograde IFT; defective chondrocyte differentiation	Intraflagellar transport; chondrocyte differentiation	IFT complex B; cilium	Growth plate chondrocyte; limb bud	Short long bones [HP:0003026]; Thoracic insufficiency [HP:0004421]	(getwan2020crisprcas9targetingttc30a pages 19-21, getwan2020crisprcas9targetingttc30a pages 16-18)
IFT52	IFT-B core subunit	IFT particle assembly defect; reduced cilia function	Intraflagellar transport; cilium assembly	IFT complex B; axoneme	Limb bud mesenchyme	Polydactyly [HP:0010442]; Short long bones [HP:0003026]	(getwan2020crisprcas9targetingttc30a pages 16-18)
WDR35 / IFT121	IFT-A component	Defective cargo retrieval; altered signaling	Retrograde ciliary transport; intraflagellar transport	IFT-A complex; ciliary base	Growth plate; kidney tubule	Narrow thorax [HP:0000774]; Renal cysts [HP:0000107]	(getwan2020crisprcas9targetingttc30a pages 16-18)
TTC21B / IFT139	IFT-A (TTC21B)	Retrograde IFT regulation; modulates SHH signaling	Intraflagellar transport; regulation of Hedgehog signaling	IFT-A complex; cilium	Growth plate chondrocyte; kidney	Polydactyly [HP:0010442]; Cystic kidney disease [HP:0000107]	(getwan2020crisprcas9targetingttc30a pages 16-18)
TRAF3IP1 / IFT54	IFT-B associated	IFT-B accessory; tubulin/IFT coupling; cilia assembly	Intraflagellar transport; cilium assembly	IFT particle; ciliary axoneme	Limb bud mesenchyme; renal epithelium	Limb anomalies; Renal involvement [HP:0000107]	(getwan2020crisprcas9targetingttc30a pages 7-9, getwan2020crisprcas9targetingttc30a pages 16-18)
IFT43	IFT-A satellite subunit	IFT-A stability / trafficking defects	Intraflagellar transport; cilium organization	IFT-A complex; cilium	Growth plate chondrocyte	SRPS features: Short ribs [HP:0000773]; Polydactyly [HP:0010442]	(getwan2020crisprcas9targetingttc30a pages 16-18)
IFT22	IFT-associated small GTPase	IFT regulation; axonemal trafficking	Intraflagellar transport; small GTPase mediated transport	Cilium; IFT particles	Limb bud mesenchyme	Polydactyly [HP:0010442]; Short long bones [HP:0003026]	(getwan2020crisprcas9targetingttc30a pages 16-18)
NEK1	NIMA-related kinase; ciliogenesis regulator	Altered cilium assembly / cell-cycle linked cilia defects	Regulation of cilium assembly; cell cycle regulation	Basal body; centrosome; cilium	Kidney tubular epithelium; growth plate	Renal cysts [HP:0000107]; Skeletal dysplasia features	(getwan2020crisprcas9targetingttc30a pages 16-18)

Table: Compact table summarizing key genes, their complexes/roles, primary mechanisms, exemplar GO processes, cellular locations, affected tissues/cell types and representative HPO phenotypes for Short-Rib Polydactyly / Short-Rib Thoracic Dysplasia, with supporting source IDs from the gathered evidence.

3) Biological Processes (GO) disrupted - Intraciliary transport; retrograde ciliary transport; cilium assembly/organization; Hedgehog signaling pathway; chondrocyte differentiation; epithelial morphogenesis of branching organs (lung); kidney tubule development. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)

4) Cellular Components - Primary cilium (axoneme, ciliary membrane), basal body/centrosome; IFT-A and IFT-B particle complexes; dynein-2 motor complex. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)

5) Disease Progression (sequence from genotype to phenotype) - Initiating lesion: Biallelic pathogenic variants in dynein-2 (e.g., DYNC2H1) or IFT-A/B genes impair retrograde/anterior IFT and/or ciliogenesis. (xiong2025anovelcompound pages 8-8, francis2023autonomousandnoncell pages 20-24) - Cellular dysfunction: Reduced/abnormal ciliation and defective trafficking in chondrocytes/mesenchyme lead to mis-specified Hh signaling gradients and growth-plate maturation defects. (francis2023autonomousandnoncell pages 16-20, getwan2020crisprcas9targetingttc30a pages 16-18) - Tissue/organ effects: Abnormal endochondral ossification yields short ribs/long bones and narrow bell-shaped thorax; limb patterning errors yield polydactyly. Ciliary dysfunction in kidney tubules predisposes to cystic changes; retinal involvement leads to degeneration in overlapping phenotypes. (francis2023autonomousandnoncell pages 20-24, getwan2020crisprcas9targetingttc30a pages 16-18) - Clinical manifestation: Perinatal respiratory failure due to thoracic insufficiency is a major determinant of lethality; spectrum overlaps with Jeune asphyxiating thoracic dystrophy and Mainzer–Saldino. (markova2022сlinicalandgenetic pages 9-11)

6) Phenotypic Manifestations (HPO) - Core skeletal: Short ribs (HP:0000773), Narrow thorax (HP:0000774), Short long bones (HP:0003026), Polydactyly (HP:0010442), Thoracic insufficiency (HP:0004421). (francis2023autonomousandnoncell pages 16-20, markova2022сlinicalandgenetic pages 9-11) - Multisystem (variable): Renal cysts (HP:0000107), Retinal degeneration (HP:0000556). (francis2023autonomousandnoncell pages 20-24)

7) Nosology and spectrum - Historical SRPS types I–IV are now encompassed by SRTD subtypes with/without polydactyly; there is broad overlap with Jeune asphyxiating thoracic dystrophy and Mainzer–Saldino syndrome, reflecting shared ciliary pathobiology. (markova2022сlinicalandgenetic pages 9-11, francis2023autonomousandnoncell pages 16-20)

8) Recent developments and latest research (2023–2024 priority) - IFT-A defects and cell autonomy: Mouse Ift140 studies (2023) delineate both cell-autonomous (e.g., limb mesenchyme, neural crest) and non–cell-autonomous contributions to structural birth defects, linking cilia loss to altered Shh signaling and thoracic/lung hypoplasia, craniofacial malformations, and polydactyly. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Dynein-2 genetics and diagnostics: Recent clinical genetics highlight recurring DYNC2H1 causal variants and use of prenatal WES/RNA-seq to resolve ambiguous ultrasound phenotypes in SRTD/Jeune families. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Mechanistic breadth in IFT disruption: Experimental systems emphasize that perturbations across IFT-B core (IFT80/IFT172) and IFT-A (TTC21B, WDR35, IFT43) converge on ciliary transport failure and Hh misregulation in skeletal lineages. bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 19-21)

9) Current applications and real-world implementations - Prenatal imaging plus genomics: Systematic second/third-trimester ultrasound recognizing short ribs, narrow thorax, and limb anomalies combined with exome sequencing is increasingly used to confirm SRPS/SRTD and counsel families. Recent dynein-2 case series and reports underscore WES utility in recurrent-affected families and variant interpretation. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Model systems for functional interpretation: IFT/dynein-2 perturbation in Xenopus and mouse models reproduces cardinal human phenotypes (polydactyly, thoracic dystrophy, renal cysts), supporting variant pathogenicity assessment frameworks. bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994; bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)

10) Expert opinions and analysis - SRTD as a ciliopathy spectrum: Reviews and compiled clinical genetics emphasize DYNC2H1 as a predominant gene in SRTD3 and underscore that respiratory failure from thoracic insufficiency drives lethality; exome sequencing is the primary tool to resolve genetic heterogeneity. (markova2022сlinicalandgenetic pages 9-11) - Quote: “Pathogenic variants of DYNC2H1… have been reported to cause SRTD3,” and phenotypes include “a narrow thorax, short ribs, shortened tubular bones.” BMC Med Genomics abstract (supportive of dynein-2 causality; see also compiled overview) (markova2022сlinicalandgenetic pages 9-11) - Developmental windows and lineage specificity: Ift140 studies indicate early embryonic windows and lineage-specific disruptions (neural crest, limb mesenchyme) underlie polydactyly/thoracic and craniofacial defects, clarifying variable phenotypic expressivity within the SRTD spectrum. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20)

11) Relevant statistics and data - Gene burden: DYNC2H1 is frequently implicated in SRTD/SRPS; curated overviews report it as the leading cause of SRTD3 and a substantial fraction of SRTD overall. (markova2022сlinicalandgenetic pages 9-11) - Multisystem frequencies: IFT140-related SRTD often associates with retinal and renal involvement, consistent with IFT-A roles and mouse knockouts demonstrating renal and ciliary defects. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 20-24)

Ontology-annotated annotations for knowledge base - Gene/Protein annotations (HGNC): DYNC2H1; DYNC2LI1; WDR60; WDR34; IFT140; WDR19 (IFT144); WDR35 (IFT121); TTC21B (IFT139); IFT172; IFT80; IFT52; TRAF3IP1 (IFT54); IFT43; IFT22; NEK1. (getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, xiong2025anovelcompound pages 8-8) - GO Processes: Intraciliary/Intraflagellar transport; Retrograde ciliary transport; Cilium assembly; Hedgehog signaling pathway; Chondrocyte differentiation; Kidney tubule development. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Cellular Components: Primary cilium; Ciliary axoneme; Basal body/centrosome; IFT-A/B complexes; Dynein-2 complex. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Cell types (CL): Growth plate chondrocyte; Limb bud mesenchymal cell; Renal tubular epithelial cell; Respiratory epithelial cell; Retinal photoreceptor cell. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Anatomy (UBERON): Limb bud; Rib/thoracic cage; Lung; Kidney; Retina. (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Phenotypes (HPO): Short ribs (HP:0000773); Narrow thorax (HP:0000774); Short long bones (HP:0003026); Polydactyly (HP:0010442); Thoracic insufficiency (HP:0004421); Renal cysts (HP:0000107); Retinal degeneration (HP:0000556). (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Chemical entities (CHEBI): Not primary; note role of tubulin post-translational modifications in ciliary function (polyglutamylation). (getwan2020crisprcas9targetingttc30a pages 16-18)

Evidence items (with URLs and dates) - Francis et al. “Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects.” bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 20-24, francis2023autonomousandnoncell pages 16-20) - Getwan et al. “CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease.” bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 18-19, getwan2020crisprcas9targetingttc30a pages 7-9, getwan2020crisprcas9targetingttc30a pages 19-21) - Xiong et al. “A novel compound heterozygous mutation in the DYNC2H1 gene in a Chinese family with Jeune syndrome.” Hereditas, Jan 2025. URL: https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Markova et al. “Clinical and genetic characteristics of skeletal ciliopathies—short-rib thoracic dysplasia.” 2022. Summary source for DYNC2H1 predominance and clinical spectrum. (markova2022сlinicalandgenetic pages 9-11)

Limitations and notes - Several mechanistic sources are preprints (2020–2023 bioRxiv) but represent authoritative groups and align with established ciliopathy biology; peer-reviewed 2023–2024 SRPS-specific systematic reviews were not captured in the present evidence set. - For comprehensive MONDO/OMIM mapping and a complete gene list, cross-reference community databases during curation.

References

(xiong2025anovelcompound pages 8-8): Sujie Xiong, Guangyao Hu, Yao Zhou, Fei Sun, and Yanlin Ma. A novel compound heterozygous mutation in the dync2h1 gene in a chinese family with jeune syndrome. Hereditas, Jan 2025. URL: https://doi.org/10.1186/s41065-025-00375-x, doi:10.1186/s41065-025-00375-x. This article has 1 citations and is from a peer-reviewed journal.
(francis2023autonomousandnoncell pages 16-20): Richard Francis, Jovenal T San Agustin, Heather L. Szabo Rogers, Cheng Cui, Julie A. Jonassen, Thibaut Eguether, John A. Follit, Cecilia W. Lo, and Gregory J. Pazour. Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132, doi:10.1101/2023.06.07.544132. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 16-18): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(markova2022сlinicalandgenetic pages 9-11): TV Markova, VM Kenis, and EV Melchenko. Сlinical and genetic characteristics of skeletal cyliopathies–short-rib thoracic dysplasia. Unknown journal, 2022.
(francis2023autonomousandnoncell pages 20-24): Richard Francis, Jovenal T San Agustin, Heather L. Szabo Rogers, Cheng Cui, Julie A. Jonassen, Thibaut Eguether, John A. Follit, Cecilia W. Lo, and Gregory J. Pazour. Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132, doi:10.1101/2023.06.07.544132. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 7-9): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 19-21): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 18-19): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.

Short-Rib Polydactyly Syndrome

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