Short-rib thoracic dysplasia 6 is the NEK1-related form of the skeletal ciliopathy spectrum, corresponding clinically to short-rib polydactyly syndrome type II (Majewski). NEK1 encodes a NIMA-related serine/threonine kinase that localises to the basal body region and coordinates the primary cilium cycle with the cell cycle; loss of functional full-length NEK1 severely reduces cilium number and alters ciliary morphology in vivo. The skeletal phenotype follows from that: the growth plate depends on primary-cilium-transduced Hedgehog signalling, so ciliary failure gives markedly short ribs, a narrow thorax, micromelia and - variably - polydactyly. Death is perinatal, from pulmonary hypoplasia secondary to the constricted thoracic cage rather than from primary lung disease. The distinguishing radiographic feature of the Majewski type is short ovoid tibiae or outright tibial agenesis, which separates it from the Beemer-Langer type (IV), where the tibiae are relatively well tubulated. That distinction turns out to be genetically meaningful: screening 13 SRP type II and seven type IV cases found NEK1 or DYNC2H1 mutations only in type II and in none of the type IV cases. Two nomenclature points a curator should hold onto. First, NEK1 is not the only gene behind the type II phenotype - homozygous NEK1 mutations were found in 5 of 13 type II cases, compound heterozygous DYNC2H1 in 4 of 12, and neither gene in 3 of 12, so the entity is genetically heterogeneous and the modern per-gene SRTD numbering is what makes this entry a single disease. Second, digenic diallelic inheritance has been proposed on the strength of a family carrying heterozygous NEK1 and DYNC2H1 mutations; that rests on individual families, not a systematic two-locus series.
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name: Short-Rib Thoracic Dysplasia 6 With or Without Polydactyly
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- SRTD6
- NEK1-related short-rib thoracic dysplasia
- Short-rib polydactyly syndrome type II
- Majewski syndrome
- Short rib-polydactyly syndrome, Majewski type
description: >-
Short-rib thoracic dysplasia 6 is the NEK1-related form of the skeletal ciliopathy
spectrum, corresponding clinically to short-rib polydactyly syndrome type II
(Majewski). NEK1 encodes a NIMA-related serine/threonine kinase that localises to the
basal body region and coordinates the primary cilium cycle with the cell cycle; loss of
functional full-length NEK1 severely reduces cilium number and alters ciliary
morphology in vivo. The skeletal phenotype follows from that: the growth plate depends
on primary-cilium-transduced Hedgehog signalling, so ciliary failure gives markedly
short ribs, a narrow thorax, micromelia and - variably - polydactyly. Death is
perinatal, from pulmonary hypoplasia secondary to the constricted thoracic cage rather
than from primary lung disease.
The distinguishing radiographic feature of the Majewski type is short ovoid tibiae or
outright tibial agenesis, which separates it from the Beemer-Langer type (IV), where
the tibiae are relatively well tubulated. That distinction turns out to be genetically
meaningful: screening 13 SRP type II and seven type IV cases found NEK1 or DYNC2H1
mutations only in type II and in none of the type IV cases.
Two nomenclature points a curator should hold onto. First, NEK1 is not the only gene
behind the type II phenotype - homozygous NEK1 mutations were found in 5 of 13 type II
cases, compound heterozygous DYNC2H1 in 4 of 12, and neither gene in 3 of 12, so the
entity is genetically heterogeneous and the modern per-gene SRTD numbering is what
makes this entry a single disease. Second, digenic diallelic inheritance has been
proposed on the strength of a family carrying heterozygous NEK1 and DYNC2H1 mutations;
that rests on individual families, not a systematic two-locus series.
disease_term:
preferred_term: short-rib thoracic dysplasia 6 with or without polydactyly
term:
id: MONDO:0009894
label: short-rib thoracic dysplasia 6 with or without polydactyly
parents:
- Ciliopathies
- Short-Rib Polydactyly Syndrome
inheritance:
- name: Autosomal recessive
description: >-
Biallelic NEK1 variants. Identified by homozygosity mapping in two consanguineous
families with Majewski-type short-rib polydactyly syndrome.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: The founding recessive mapping result.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases."
explanation: Confirms biallelic NEK1 involvement in an independent case series.
- name: Digenic diallelic (NEK1/DYNC2H1)
description: >-
A proposed second inheritance mode in which heterozygous mutations at two ciliopathy
loci combine. It rests on individual families rather than a systematic two-locus
screen, and one prenatal case with a single paternal-origin NEK1 splice variant and no
identified second mutation is consistent with - but does not establish - the same
idea. Treat it as proposed, not settled.
inheritance_term:
preferred_term: Digenic inheritance
term:
id: HP:0010984
label: Digenic inheritance
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: >-
Graded PARTIAL - a single additional family substantiating a pre-existing proposal,
which is suggestive rather than conclusive.
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Molecular analysis of fetal tissues showed a paternal-origin heterozygous splice site mutation in intron 7 (c.465-1 G>A) in the NEK1 gene, but no mutations in the genes of WDR35, DYNC2H1, IFT80, EVC and EVC2. The NEK1 mutation causes an alteration of the splice acceptor site of intron 7 (IVS7-1 G>A). No second mutation was identified."
explanation: >-
A clinically typical case with only one identified NEK1 allele and no second hit in
the screened ciliopathy genes. Consistent with an unfound second allele or with a
non-classical inheritance mechanism; it distinguishes neither.
pathophysiology:
- name: NEK1 Loss of Function
description: >-
Biallelic NEK1 variants abolish functional full-length protein. NEK1 is a
serine/threonine kinase of the NIMA-related family with proposed roles in DNA
double-strand break repair, neuronal development and cell-cycle-associated
ciliogenesis. Reported alleles include splice-site variants disrupting the acceptor
site of intron 7.
biological_scale: MOLECULAR
genes:
- preferred_term: NEK1
term:
id: hgnc:7744
label: NEK1
molecular_functions:
- preferred_term: protein serine/threonine kinase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004674
label: protein serine/threonine kinase activity
downstream:
- target: Defective Ciliogenesis
causal_link_type: DIRECT
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: Defines the gene product and its proposed functions.
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The NEK1 mutation causes an alteration of the splice acceptor site of intron 7 (IVS7-1 G>A)."
explanation: An example of the splice-disrupting allele class.
- name: Defective Ciliogenesis
description: >-
Loss of NEK1 severely reduces cilium number and alters ciliary morphology in vivo.
Mechanistically NEK1 sits at the basal body, and the relationship is dose-sensitive in
both directions: overexpressing NEK1 also inhibits ciliogenesis in cultured epithelial
cells, and cilium number is dramatically reduced in kat2J mouse embryonic fibroblasts.
That two-sided sensitivity is why NEK1 is thought to link cell-cycle progression to
the cilium cycle rather than simply to build cilia.
biological_scale: CELLULAR
biological_processes:
- preferred_term: cilium assembly
modifier: DECREASED
term:
id: GO:0060271
label: cilium assembly
cellular_components:
- preferred_term: centriole
term:
id: GO:0005814
label: centriole
downstream:
- target: Impaired Growth Plate Chondrogenesis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo."
explanation: The primary ciliary phenotype in patient material.
- reference: PMID:18387364
reference_title: "The mammalian Nek1 kinase is involved in primary cilium formation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We demonstrated herein that Nek1 is localized to basal body region and that Nek1 overexpression inhibits ciliogenesis in Madin-Darby canine kidney epithelial cells."
explanation: Localises NEK1 to the basal body and shows overexpression also impairs ciliogenesis.
- reference: PMID:18387364
reference_title: "The mammalian Nek1 kinase is involved in primary cilium formation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The number of primary cilia is dramatically reduced in kat2J mouse embryonic fibroblasts culture."
explanation: Independent confirmation of reduced ciliation in a Nek1-deficient mouse line.
- reference: PMID:18387364
reference_title: "The mammalian Nek1 kinase is involved in primary cilium formation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "It is thus hypothesized that Nek1 links cell cycle progression and the PC cycle."
explanation: >-
Graded PARTIAL - explicitly stated as a hypothesis by its authors, and it is the
interpretation that makes sense of loss and overexpression both being disruptive.
- name: Impaired Growth Plate Chondrogenesis
description: >-
The primary cilium transduces Hedgehog signalling, on which endochondral ossification
at the growth plate depends. Ciliary failure therefore produces the disproportionate
shortening of ribs and long bones and the digit patterning defects that define the
disorder. The founding study suggests the severity of the resulting skeletal phenotype
tracks the degree of defective microtubule or centriole elongation, which would place
NEK1 disease and the other skeletal ciliopathies on one mechanistic continuum rather
than making them separate entities.
biological_scale: TISSUE
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
downstream:
- target: Thoracic Constriction
causal_link_type: DIRECT
notes: >-
This node carries no Hedgehog descriptor. Reduced Hedgehog signalling downstream of
ciliary failure is well established in the skeletal ciliopathies as a group, but no
reference cached for this entry measures or states it for NEK1, so annotating it here
would assert as fact what the entry can only reason toward. The inference belongs in
the description, where it reads as reasoning. A source reporting Hedgehog output in
NEK1-deficient tissue is what a smoothened signaling pathway descriptor would need.
evidence:
- reference: PMID:24854045
reference_title: "Majewski syndrome (short-rib polydactyly syndrome type II): Prenatal diagnosis and histological features of chondral growth plate, liver and kidneys."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histological examination of the femoral epypheseal chondral plate showed an expanded and irregular hypertrophic zone."
explanation: >-
The histological lesion at the growth plate itself, in an autopsied Majewski case -
an expanded, disorganised hypertrophic zone. This is the direct tissue-level evidence
for the node, which previously rested only on a proposed genotype-severity
correlation.
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype"
explanation: >-
Graded PARTIAL - a proposed genotype-severity correlation, stated as a suggestion
rather than a measured relationship.
- name: Thoracic Constriction
description: >-
Markedly short ribs give a small, rigid, bell-shaped thorax. This is the skeletal
lesion expressed at the level of the chest wall, and it is what the surgical
interventions attempted at the survivable end of the spectrum are aimed at.
biological_scale: TISSUE
locations:
- preferred_term: thoracic cavity
term:
id: UBERON:0002224
label: thoracic cavity
downstream:
- target: Pulmonary Hypoplasia
causal_link_type: DIRECT
evidence:
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance."
explanation: >-
Establishes the short ribs that constrict the thorax. Graded as support for the rib
lesion specifically; it is a group-level definition and does not by itself assert the
mechanical consequence, which is why that claim now sits on the edge below.
- name: Pulmonary Hypoplasia
description: >-
Lungs constrained by a thorax that cannot accommodate them, giving respiratory
insufficiency that is the proximate cause of death. The disease sits within thoracic
insufficiency syndrome, defined as any disorder in which the chest cannot support
normal pulmonary development - so the limitation is mechanical rather than intrinsic
lung disease, and the respiratory distress follows from thoracic morphology.
biological_scale: ORGANISM
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
evidence:
- reference: PMID:23985472
reference_title: "Jeune syndrome: considerations for management of asphyxiating thoracic dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Children with JS present with variable degrees of respiratory distress, frequently lethal in the neonatal period."
explanation: >-
The respiratory outcome and its lethality, which is the claim this node makes. Graded
PARTIAL because it is stated for Jeune syndrome rather than for NEK1 disease.
- reference: PMID:19610081
reference_title: "Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: Evaluation and classification of 13 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "respiratory distress was observed in eight patients and proved lethal in six"
explanation: >-
Puts numbers on the lethality in a patient series - eight of eleven followed
postnatally had respiratory distress and six died of it. Graded PARTIAL for the same
cross-disease reason.
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the disease is part of the heterogeneous spectrum of thoracic insufficiency syndrome (TIS), which includes any disorder resulting in an inability of the chest to support normal pulmonary development, function, and growth"
explanation: >-
The mechanical claim this node makes, stated as the definition of thoracic
insufficiency syndrome: the chest fails to support pulmonary development, so the lung
limitation is a consequence of the chest wall rather than intrinsic lung disease.
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Notably, the respiratory distress is caused by the anomalous morphology of the thorax, predisposing to a progressive restrictive respiratory insufficiency"
explanation: >-
States the direction of causation explicitly - thoracic morphology causes the
respiratory distress - which is what distinguishes this node from independent lung
disease.
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Highly symptomatic patients experience severe lung hypoplasia, pulmonary hypertension, and restrictive respiratory insufficiency."
explanation: >-
Names lung hypoplasia itself, which is what this node is called, rather than only the
respiratory outcome it produces.
notes: >-
Every evidence item on this node is graded PARTIAL because all of them describe Jeune
syndrome or thoracic insufficiency syndrome as a group rather than NEK1 disease or
Majewski syndrome specifically. A NEK1-specific or Majewski-specific measurement of
lung volume or histology is what would let them be graded SUPPORT.
phenotypes:
- name: Pulmonary Hypoplasia
category: Respiratory
description: >-
Underdeveloped lungs, the consequence of a thorax that cannot support normal pulmonary
growth, and the finding behind the perinatal lethality of this disorder.
phenotype_term:
preferred_term: Pulmonary hypoplasia
term:
id: HP:0002089
label: Pulmonary hypoplasia
evidence:
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Highly symptomatic patients experience severe lung hypoplasia, pulmonary hypertension, and restrictive respiratory insufficiency."
explanation: >-
Names lung hypoplasia in the severely affected. Graded PARTIAL and carrying no
frequency because it is stated for Jeune syndrome as a group rather than for NEK1
disease, and because "highly symptomatic patients" is not a denominator.
notes: >-
Deliberately carries no frequency. The available statement is qualitative and applies
to Jeune syndrome at the survivable end of this group; nothing cached gives a
proportion for NEK1 or Majewski disease, and a FrequencyEnum value here would assert a
band no source supports.
- name: Short Ribs
category: Skeletal
description: Markedly short ribs, the defining skeletal feature.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Short ribs
term:
id: HP:0000773
label: Short ribs
evidence:
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs"
explanation: Short ribs as a defining feature of the SRP group.
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fetal ultrasound revealed short ribs, short limbs, absence of tibiae, polydactyly, syndactyly and choroid plexus cysts."
explanation: Prenatal sonographic documentation in a NEK1-confirmed fetus.
- name: Narrow Chest
category: Skeletal
description: Narrow, constricted thoracic cage secondary to the short ribs.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Narrow chest
term:
id: HP:0000774
label: Narrow chest
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a fetus was delivered with facial dysmorphism, a median cleft lip, a narrow chest, micromelia, aplasia of tibiae, hypoplastic nails, syndactyly and postaxial polydactyly"
explanation: Postnatal confirmation of the narrow chest in a NEK1-confirmed case.
- name: Abnormal Tibia Morphology
category: Skeletal
description: >-
Short ovoid tibiae or outright tibial agenesis. This is the radiographic feature that
distinguishes Majewski-type from Beemer-Langer-type short-rib polydactyly syndrome,
where the tibiae are relatively well tubulated - and that distinction turns out to
track the genetics, since NEK1 and DYNC2H1 were excluded in all type IV cases tested.
frequency: FREQUENT
phenotype_term:
preferred_term: Short ovoid tibiae or tibial agenesis
term:
id: HP:0002992
label: Abnormal tibia morphology
evidence:
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae."
explanation: Defines the tibial finding as the type II/IV radiographic discriminator.
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Tibial aplasia, choroid plexus cysts and polycystic kidneys can be prominent prenatal ultrasound findings of type II SRPS."
explanation: Tibial aplasia as a prenatally detectable feature.
notes: >-
The source describes "short ovoid tibiae or tibial agenesis" - a disjunction in which
only the second limb is absence. HP:0002992 is bound because it is the most specific
term that covers the whole disjunction; the narrower HP:0009556 would encode the severe
end of a range as though it were the entire finding. Splitting into Short tibia
(HP:0005736) and Absent tibia (HP:0009556) would be more informative and awaits a
source giving separate frequencies for the two forms, since the split cannot be made
without inventing a distribution between them.
- name: Postaxial Polydactyly
category: Skeletal
description: >-
Polydactyly, variably present - which is why the modern disease name carries "with or
without polydactyly" rather than treating it as obligatory.
frequency: FREQUENT
phenotype_term:
preferred_term: Postaxial polydactyly
term:
id: HP:0100259
label: Postaxial polydactyly
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoplastic nails, syndactyly and postaxial polydactyly"
explanation: Postaxial polydactyly in a NEK1-confirmed fetus.
- name: Micromelia
category: Skeletal
description: Disproportionate limb shortening.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Micromelia
term:
id: HP:0002983
label: Micromelia
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a narrow chest, micromelia, aplasia of tibiae"
explanation: Micromelia documented at delivery.
- name: Median Cleft Upper Lip
category: Craniofacial
description: Median cleft lip, part of the craniofacial involvement.
frequency: FREQUENT
phenotype_term:
preferred_term: Median cleft upper lip
term:
id: HP:0000161
label: Median cleft upper lip
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a fetus was delivered with facial dysmorphism, a median cleft lip, a narrow chest"
explanation: Median cleft lip in a NEK1-confirmed case.
- name: Polycystic Kidney Dysplasia
category: Renal
description: >-
Renal cystic disease, detectable prenatally. It is mechanistically coherent rather
than incidental: NEK1 was first characterised through murine polycystic kidney
disease, and the same ciliary defect underlies both the skeletal and the renal
phenotype.
frequency: FREQUENT
phenotype_term:
preferred_term: Polycystic kidney dysplasia
term:
id: HP:0000113
label: Polycystic kidney dysplasia
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 21 weeks of gestation, polycystic kidneys were found."
explanation: Prenatal renal cystic disease in a NEK1-confirmed fetus.
- reference: PMID:18387364
reference_title: "The mammalian Nek1 kinase is involved in primary cilium formation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Murine mutants for the NRKs, nek1 (kat mice) suffer from PKD, suggesting that it may be involved in cilium control."
explanation: The murine renal phenotype that first linked NEK1 to ciliary function.
- reference: PMID:35081715
reference_title: "Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos."
explanation: >-
A pharmacological phenocopy, and the reason it is worth curating alongside the mouse
and human genetics: acute chemical inhibition of Nek1 in a third species produces the
renal cystic phenotype, so it does not depend on a developmental compensation or a
strain background the way a germline mutant does.
- name: Syndactyly
category: Skeletal
description: Syndactyly accompanying the polydactyly.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "short ribs, short limbs, absence of tibiae, polydactyly, syndactyly and choroid plexus cysts"
explanation: Syndactyly on prenatal ultrasound.
histopathology:
- name: Femoral epiphyseal growth plate
description: >-
Postmortem histology of the femoral growth plate shows an expanded and irregular
hypertrophic zone. This is the tissue-level correlate of the impaired endochondral
ossification the pathograph asserts: the hypertrophic chondrocytes accumulate instead
of being replaced in orderly columns, which is what produces short bones from a growth
plate that is present but not working.
evidence:
- reference: PMID:24854045
reference_title: "Majewski syndrome (short-rib polydactyly syndrome type II): Prenatal diagnosis and histological features of chondral growth plate, liver and kidneys."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histological examination of the femoral epypheseal chondral plate showed an expanded and irregular hypertrophic zone."
explanation: The growth-plate lesion itself, in an autopsied Majewski case.
- name: Kidney and liver
description: >-
Cortico-medullary renal cysts with portal fibrosis of the liver - the visceral
ciliopathy findings that accompany the skeletal phenotype and place this disorder in
the ciliopathy group rather than among isolated skeletal dysplasias.
evidence:
- reference: PMID:24854045
reference_title: "Majewski syndrome (short-rib polydactyly syndrome type II): Prenatal diagnosis and histological features of chondral growth plate, liver and kidneys."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Moreover, characteristic cortico-medullary cysts of both kidneys and portal fibrosis were also demonstrated; findings consistent with the broad phenotypic spectrum of this rare skeletal disease."
explanation: >-
Renal cystic disease and portal fibrosis at autopsy, the classic ciliopathy visceral
pair.
treatments:
- name: Perinatal Palliative Care
description: >-
Majewski-type short-rib polydactyly syndrome is lethal in the perinatal period from
respiratory failure, and no treatment alters that. Palliative care and the counselling
that goes with a prenatal or perinatal diagnosis are what is actually offered. This
section is short because the disorder is lethal, not because management was not looked
for.
therapeutic_modality: OTHER
treatment_term:
preferred_term: palliative therapy
term:
id: NCIT:C15292
label: Palliative Therapy
notes: >-
No cached reference reports a palliative-care protocol for this specific disorder, so
this entry carries no evidence item rather than a quote that does not say what the
entry claims. Its basis is the lethality documented elsewhere in this file.
- name: Genetic Counselling and Prenatal Diagnosis
description: >-
Counselling with a 25% recurrence risk for the autosomal recessive form, and prenatal
ultrasound that can detect the phenotype in the second trimester. Counselling is
load-bearing here rather than routine: recurrence risk is not straightforwardly 25% in
every family, because a digenic diallelic mechanism involving NEK1 and DYNC2H1 has been
proposed, and a negative NEK1 result does not exclude the clinical diagnosis.
therapeutic_modality: OTHER
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:22482978
reference_title: "Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Tibial aplasia, choroid plexus cysts and polycystic kidneys can be prominent prenatal ultrasound findings of type II SRPS."
explanation: >-
The prenatally detectable findings on which prenatal diagnosis, and therefore
counselling in a subsequent pregnancy, rests.
- name: Thoracic Expansion Surgery
description: >-
Progressive internal distraction of the sternum, used at the non-lethal end of the
short-rib thoracic dysplasia group. Curated with an explicit boundary: this is a Jeune
syndrome intervention, reported in two patients, and no NEK1 or Majewski-type patient
has been treated this way because they do not survive to be candidates. It is here
because the surgical target - the constricted thorax - is the same node, and because a
reader asking whether anything can be done for the chest should find the answer with
its limits attached rather than find nothing.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: thoracoplasty
term:
id: NCIT:C86923
label: Thoracoplasty
target_mechanisms:
- target: Thoracic Constriction
treatment_effect: MODULATES
description: >-
Enlarges the thoracic cavity mechanically. It does not touch the ciliary or
growth-plate lesion upstream, so it is palliative of the constriction rather than
disease-modifying.
evidence:
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this study, we analyzed and presented our preliminary experience with a device for progressive internal distraction of the sternum (PIDS) in patients with symptomatic JS."
explanation: >-
Graded PARTIAL. The intervention is real and reported, but in Jeune syndrome rather
than in Majewski-type disease or in any NEK1 patient.
- reference: PMID:37822322
reference_title: "Case report: A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome (asphyxiating thoracic dystrophy): preliminary experience and literature review of surgical techniques."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We obtained promising results regarding the safety and effectiveness of this less-invasive device for PIDS in patients with symptomatic JS. Further studies on long-term outcomes are needed to validate these findings."
explanation: >-
The authors' own hedge, quoted rather than paraphrased - promising in two patients,
with long-term outcomes still needed. That is the correct strength for a
cross-disease extrapolation.
genetic:
- name: NEK1
notes: >-
NEK1 accounts for a minority of Majewski-type cases - homozygous NEK1 mutations in
5 of 13, with compound heterozygous DYNC2H1 in 4 of 12 and neither gene in 3 of 12.
The phenotype is therefore genetically heterogeneous and a negative NEK1 result does
not exclude the clinical diagnosis. Note also that NEK1 is separately established as
an amyotrophic lateral sclerosis risk gene; the ciliopathy and ALS roles are distinct
claims and should not be conflated. Zygosity and allele class separate them: the
skeletal disease is autosomal recessive with biallelic loss of function, while the ALS
association is a heterozygous risk effect including a specific missense variant.
Nothing here should be read as saying that carriers of a Majewski allele are at ALS
risk, or that the ciliary mechanism curated here operates in motor neurons.
relationship_type: CAUSATIVE
gene_term:
preferred_term: NEK1
term:
id: hgnc:7744
label: NEK1
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia"
explanation: The founding gene-disease association.
- reference: PMID:29929116
reference_title: "NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR."
explanation: >-
Substantiates the separation asserted in these notes. The ALS role runs through the
DNA damage response, a different function of the same protein from the ciliogenesis
role curated in this entry's pathograph, so the two disease associations are not one
mechanism seen twice.
- reference: PMID:29929116
reference_title: "NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS"
explanation: >-
The authors' own result rather than their recitation of prior genetics. The ALS
pathomechanism they identify converges with other ALS genes, not with the ciliary
route curated here, which is what keeps the two NEK1 disease associations separate.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations."
explanation: Independent confirmation, and explicit statement that NEK1 is one gene among several.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity."
explanation: Quantifies the unexplained fraction and the clean separation from type IV.
- reference: PMID:37585529
reference_title: "Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases."
explanation: >-
Graded NO_EVIDENCE deliberately. This says nothing about the skeletal ciliopathy; it
is here to substantiate the pleiotropy statement in the notes, which was previously
unevidenced prose. Quantifying the ALS role at 2-3% of cases shows how large and how
separate that literature is.
- reference: PMID:38986433
reference_title: "Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility."
explanation: >-
Also NO_EVIDENCE for the skeletal claim. Quoted because it names the allele class
behind the ALS association - a heterozygous missense risk variant - which is what
distinguishes it from the biallelic loss of function that causes this disorder.
- name: DYNC2H1
notes: >-
DYNC2H1 encodes the cytoplasmic dynein 2 heavy chain that drives retrograde
intraflagellar transport, so it acts on the same ciliary process as NEK1. It is
curated here as COOPERATING rather than CAUSATIVE for a specific reason: in the
Majewski series it accounts for its own biallelic cases (compound heterozygous in 4 of
12), which would make it causative for those patients, but this entry is keyed to
MONDO:0009894, the NEK1-defined disorder. What earns it a place here is the digenic
observation - a family carrying heterozygous mutations in both genes - which is the
claim the disease-level inheritance block makes and which the genetic section
previously did not know about.
relationship_type: COOPERATING
gene_term:
preferred_term: DYNC2H1
term:
id: hgnc:2962
label: DYNC2H1
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: >-
The digenic observation, which is what makes DYNC2H1 a cooperating locus here rather
than simply another gene for the same clinical picture.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance."
explanation: >-
Independent restatement of the same double-heterozygous case, which is the whole
evidential basis for the digenic claim - one family, reported twice.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases."
explanation: >-
Graded PARTIAL. It quantifies DYNC2H1's independent contribution to the Majewski
phenotype, which is real but belongs to a different MONDO concept than this entry.
diagnosis:
- name: Whole exome sequencing
description: >-
WES is established as an efficient first-line method for the short-rib thoracic
dystrophies. Across 11 affected individuals it identified biallelic mutations in six
confirmed SRTD genes including NEK1 in 10, giving 90.9% sensitivity, with specificity
above 99% against 993 unaffected individuals. That performance matters here because
the alternative - iterative Sanger sequencing across 14 genes and 398 exons - is
expensive enough that it is often simply not undertaken.
evidence:
- reference: PMID:25492405
reference_title: "Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%."
explanation: Establishes WES sensitivity, with NEK1 among the genes detected.
- reference: PMID:25492405
reference_title: "Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken."
explanation: The comparator that makes WES the recommended approach.
animal_models:
- name: kat2J Nek1-deficient mouse
species: Mouse
genotype: Nek1 kat2J homozygous (spontaneous mutant)
publication: PMID:25030234
description: >-
A spontaneous Nek1 mutant line originally characterised as a polycystic kidney disease
model rather than a skeletal one. Homozygotes show aberrant kidney development before
gross cysts appear - thin cortical zones, immature glomeruli, excessive apoptosis -
then postnatal cysts throughout the nephron. Cilia lining the cysts are morphologically
diverse, some unusually long and some multiple.
genes:
- preferred_term: NEK1
term:
id: hgnc:7744
label: NEK1
modeled_mechanisms:
- target: Defective Ciliogenesis
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Reproduces the ciliary defect in an intact animal, both as reduced cilium number in
embryonic fibroblasts and as abnormal ciliary morphology in cyst-lining cells.
limitations: >-
Note the direction is not simply "fewer cilia": in cyst-lining cells some cilia are
unusually long and some cells carry several, which is a patterning and length-control
defect rather than a failure to ciliate. That is consistent with NEK1 coordinating
the cilium cycle, but it means the model's ciliary phenotype is not a clean
quantitative match to the reduced ciliation reported in patient material.
readouts:
- name: Primary cilium number in embryonic fibroblasts
target: Defective Ciliogenesis
direction: DECREASED
interpretation: Reduced ciliation in Nek1-deficient cells.
evidence:
- reference: PMID:18387364
reference_title: "The mammalian Nek1 kinase is involved in primary cilium formation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The number of primary cilia is dramatically reduced in kat2J mouse embryonic fibroblasts culture."
explanation: The quantitative ciliary measurement in this model.
- name: Ciliary morphology in cyst-lining cells
target: Defective Ciliogenesis
direction: ALTERED
interpretation: >-
Length and number dysregulation rather than absence, supporting a cilium-cycle
coordination role.
evidence:
- reference: PMID:25030234
reference_title: "Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The primary cilia of cells lining cysts in kat2J homozygous mice are morphologically diverse: in some cells they are unusually long and in others there are multiple cilia of varying lengths."
explanation: The morphological description behind this readout.
evidence:
- reference: PMID:25030234
reference_title: "Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Nek1 is the primary protein inactivated in kat2J mouse models of PKD."
explanation: Establishes the model's genetic basis.
notes: >-
This model carries no link to Impaired Growth Plate Chondrogenesis, deliberately. The
cited characterisation is entirely renal: no rib, thorax, limb or growth-plate phenotype
is reported. That is an absence of reported skeletal assessment, not a documented normal
skeleton, and FAILS_TO_RECAPITULATE is a substantive negative claim that exports consume
- encoding "nobody looked" as "the model fails" would put a claim into the graph that no
source makes. The gap is recorded in the nek1_srtd6_no_skeletal_model discussion
instead, which is where an unanswered question belongs. A study that assays the kat2J
skeleton and finds it normal is the evidence such a link would need.
evidence:
- reference: PMID:25030234
reference_title: "Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the embryonic kidney, Nek1 expression is most prominent in cells that will become podocytes and proximal tubules."
explanation: Expression data supporting the model's relevance to the renal component of the disorder.
discussions:
- discussion_id: nek1_srtd6_no_skeletal_model
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Why has the Nek1 mouse been characterised almost entirely as a kidney model when the
human NEK1 disorder is defined by a lethal skeletal phenotype, and does a Nek1 mouse
reproduce the short ribs and thoracic constriction at all?
attaches_to:
- pathophysiology#Impaired Growth Plate Chondrogenesis
- pathophysiology#Thoracic Constriction
- pathophysiology#Pulmonary Hypoplasia
rationale: >-
The kat2J line predates the human skeletal association by decades and entered the
literature as a polycystic kidney disease model, so its characterisation followed the
kidney. The result is that the organ system carrying essentially all of the human
mortality has no reported model phenotype. Three readings are possible and they are not
equivalent: the mouse skeleton may be genuinely spared, in which case there is a
species difference in how growth-plate chondrocytes depend on NEK1; the skeletal
phenotype may simply never have been looked for; or perinatal lethality in the severe
human alleles may have no murine counterpart because kat2J is hypomorphic rather than
null. Distinguishing them needs only skeletal preparations and rib measurements on
existing animals. Until then, nothing in the model literature tests the growth-plate
Hedgehog mechanism this entry proposes.
evidence:
- reference: PMID:25030234
reference_title: "Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our studies indicate that Nek1 deficiency leads to disordered kidney maturation, and cysts throughout the nephron."
explanation: The scope of the model's published characterisation - renal, not skeletal.
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia"
explanation: >-
The human phenotype is an osteochondrodysplasia, which is precisely what the model
literature does not report on.
- discussion_id: nek1_srtd6_unexplained_type_ii_cases
kind: KNOWLEDGE_GAP
prompt: >-
What causes the quarter of Majewski-type short-rib polydactyly cases in which neither
NEK1 nor DYNC2H1 is mutated?
attaches_to:
- genetic#NEK1
rationale: >-
In the largest targeted screen, NEK1 and DYNC2H1 were both excluded in 3 of 12 type II
cases. That is not a rounding error, and the study reports a clinical correlate worth
following: holoprosencephaly and polymicrogyria were the main difference between the
mutation-positive and mutation-negative groups. A brain malformation segregating with
the unexplained cases suggests they may not be the same entity at all, rather than
being NEK1-negative instances of it - which would matter for whether they belong under
this MONDO term. Whole exome sequencing is already established as sensitive and
specific in this disease group, so the cohort exists and the method exists.
evidence:
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group."
explanation: >-
The clinical signal distinguishing the unexplained cases, and the reason to suspect
they are a separate entity.
- reference: PMID:22499340
reference_title: "NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases."
explanation: Quantifies the unexplained fraction.
Overview. Short-rib thoracic dysplasia 6 with or without polydactyly (SRTD6) is an autosomal recessive skeletal ciliopathy caused by biallelic mutation of the NEK1 gene on chromosome 4q33. It belongs to the short-rib thoracic dysplasia (SRTD) group of disorders — historically also called short rib–polydactyly syndrome (SRPS) — and corresponds specifically to short rib–polydactyly syndrome type II, Majewski type. SRTD6 is a lethal osteochondrodysplasia in its classic (homozygous-null) presentation, characterized by a severely constricted, narrow thoracic cage; short, horizontally oriented ribs; short long bones; and a "trident" (three-pronged) acetabular roof, together with variable polydactyly and multiorgan visceral anomalies (OMIM #263520; DOID:0110092).
Key identifiers: - OMIM: #263520 — SHORT-RIB THORACIC DYSPLASIA 6 WITH OR WITHOUT POLYDACTYLY; SRTD6 (omim.org/entry/263520) - MONDO: MONDO:0009894 - Disease Ontology: DOID:0110092 - ICD-10-CM: Q77.2 (Asphyxiating thoracic dysplasia) - Gene: NEK1 (HGNC), OMIM gene entry 604588, chr4q33 - UMLS/MedGen concept: C0024507 (NCBI GTR)
Synonyms: Majewski syndrome; Short rib-polydactyly syndrome, type II (SRPS2); Short rib-polydactyly syndrome type IIA (SRPS2A); Polydactyly with neonatal chondrodystrophy, type II; Short-rib polydactyly syndrome type Majewski (JAX DOID browser).
Data provenance: Knowledge is derived almost entirely from aggregated disease-level resources (OMIM, GeneReviews-style skeletal-ciliopathy reviews, structured case-report literature and prenatal case series) rather than large EHR cohorts — this is a rare Mendelian disorder without a dedicated national registry, so most quantitative data (mutation counts, cilia measurements) come from individual research cohorts/case series of a few dozen families total (Thiel et al. 2011, PMID:21211617; El Hokayem et al. 2012, PMID:22499340).
Primary genetic cause. SRTD6 is caused by homozygous or compound heterozygous loss-of-function mutation in NEK1, which encodes a NIMA-related serine/threonine kinase (NEK1) required for cilium assembly, and separately implicated in DNA double-strand-break repair/checkpoint control and neuronal development (OMIM #263520; Thiel et al. 2011). NEK1 has relatively high expression in the growth plate, consistent with the skeletal phenotype.
Founding mutations. In the discovery study (Thiel et al., AJHG 2011, PMID:21211617), homozygosity mapping in two consanguineous families identified: - Family 1: homozygous nonsense mutation c.379C>T (p.Arg127X) - Family 2: homozygous splice-site mutation c.869-2A>G - Family 3: heterozygous frameshift insertion c.1640dup in NEK1 together with a heterozygous missense variant in DYNC2H1
Digenic/oligogenic inheritance. A distinctive etiologic feature of SRTD6 is documented digenic diallelic inheritance: a proband can be affected by combined heterozygosity for one loss-of-function NEK1 allele and one pathogenic DYNC2H1 allele, producing "combined haploinsufficiency of cilia formation and intraflagellar transport (IFT)" (Thiel et al. 2011). This was substantiated in a larger follow-up cohort: El Hokayem et al. (J Med Genet 2012, PMID:22499340) screened 13 SRP type II (Majewski) and 7 SRP type IV (Beemer-Langer) cases, finding homozygous NEK1 mutations in 5/13 type II cases, compound heterozygous DYNC2H1 mutations in 4/12 type II cases, and one case with double heterozygosity across both genes — while both genes were excluded in all type IV (Beemer-Langer) cases, establishing that NEK1/DYNC2H1 involvement is specific to the Majewski subtype. The authors noted residual genetic heterogeneity, since neither gene explained all screened cases, implying additional unidentified causal genes remain. Mutation-negative SRP type II cases in that cohort notably presented with holoprosencephaly and polymicrogyria, absent in mutation-positive cases — suggesting phenotypic clues to underlying gene.
Risk factors: - Genetic: consanguinity substantially raises risk given the autosomal recessive, homozygous-null mechanism seen in the founding families. - Environmental: No environmental, infectious, or lifestyle risk factors are established; this is a purely monogenic/digenic ciliopathy. - Gene-environment interaction: None reported.
Protective factors: None specifically described for SRTD6. In the broader ciliopathy spectrum, allelic severity is thought to be genotype-dependent — hypomorphic (partial-function) alleles of ciliary genes generally produce milder, non-lethal SRTD phenotypes (e.g., Mainzer-Saldino, isolated Jeune-type disease) versus complete loss-of-function alleles producing lethal Majewski-type disease, though this specific genotype-severity correlation has not been formally established for NEK1 itself.
Because SRTD6 aggregates clinical data across a small number of published families/case reports, phenotype frequencies below are qualitative characterizations from the SRTD/SRPS Majewski-type literature rather than large-cohort percentages.
Skeletal phenotype (core, congenital/prenatal onset): - Narrow, constricted thoracic cage — HP:0000774 (Narrow chest) - Short ribs — HP:0000773 (Short ribs) - Short-limbed dwarfism/micromelia — HP:0004970 (Mesomelia) / HP:0009824 (Progressive shortening of the extremities) - Disproportionately short, ovoid tibiae or tibial agenesis (the most distinctive Majewski-type finding, distinguishing it from other SRP subtypes) — HP:0005843 (Micromelia); HP:0009825 - Polydactyly (pre- and postaxial), variably present — HP:0100259 (Postaxial polydactyly) / HP:0001161 (Preaxial polydactyly) - Trident-shaped acetabular roof on radiography — HP:0003026 (Trident acetabular roof)
Craniofacial: - Dysmorphic facial features — HP:0001999 - Cleft lip/palate (part of the broader SRTD non-skeletal spectrum) — HP:0000175 (Cleft palate) / HP:0100333 (Unilateral cleft lip) - Relatively proportionate head size at birth progressing to microcephaly
Visceral/organ anomalies: - Cystic/polycystic kidney disease with dilated collecting tubules and glomeruli of variable size — HP:0000113 (Polycystic kidney dysplasia) - Intestinal malrotation — HP:0002566 - Congenital heart defects — HP:0001627 - Hepatic anomalies (periportal fibrosis, biliary dysgenesis characteristic of the broader ciliopathy spectrum) — HP:0006560 - Lingual/gingival hamartomas reported in a substantial minority of NEK1-related cases - Genital anomalies
Growth: Severe intrauterine growth restriction is characteristic of the Majewski (type II) presentation (search summary of Tonni et al. 2014, PMID:24854045).
Onset/severity/progression. Onset is prenatal/congenital in essentially all cases; the classic homozygous-null presentation is uniformly severe and lethal in the perinatal/neonatal period due to pulmonary hypoplasia secondary to the restrictive thoracic cage (respiratory insufficiency). At least one report describes "a short rib polydactyly syndrome overlapping both lethal and nonlethal types" (PMID:22876582), suggesting a phenotypic continuum exists at the milder end even within Majewski-type presentations, potentially correlating with residual NEK1/DYNC2H1 function in digenic or hypomorphic cases.
Quality of life impact. For the lethal neonatal presentation, QOL data are not applicable given perinatal mortality; for surviving/milder cases (analogous non-lethal SRTD forms), impact centers on chronic respiratory insufficiency, orthopedic disability from limb shortening, and renal/hepatic morbidity — but disease-specific QOL instruments have not been applied to this specific ultra-rare entity.
Causal gene: NEK1 (HGNC:7744; NCBI Gene ID 4750), OMIM *604588, chromosome 4q33.
Variant spectrum documented in the literature: | Variant | Type | Zygosity | Source | |---|---|---|---| | c.379C>T (p.Arg127X) | Nonsense | Homozygous | Thiel 2011, Family 1 | | c.869-2A>G | Splice-site (canonical acceptor) | Homozygous | Thiel 2011, Family 2 | | c.1640dup | Frameshift insertion | Heterozygous (digenic with DYNC2H1) | Thiel 2011, Family 3 | | c.2255A>G (p.Glu752Gly) | Missense | — | ClinVar RCV000625335 | | c.1020+1G>A | Splice-site | — | ClinVar RCV003106460 |
Digenic partner gene: DYNC2H1 (cytoplasmic dynein 2 heavy chain 1), OMIM 603297, encoding the retrograde IFT motor protein; biallelic DYNC2H1 mutations alone cause the allelic disorder SRTD3/short-rib polydactyly type I (Saldino-Noonan). El Hokayem et al. found compound heterozygous DYNC2H1* mutations independently causal in 4/12 SRTD6-consistent cases, and demonstrated true digenic (both-gene) inheritance in at least one further case.
Functional consequence: Loss-of-function (nonsense/frameshift/splice-disrupting) — patient fibroblasts show a severe ciliogenesis defect: only ~27% of cells possessed cilia versus 92% in controls; residual cilia averaged 1.7 ± 0.7 μm in length versus 6.2 ± 1.2 μm in controls, with a "severely reduced length, broad base, and thin apex," and electron microscopy showed ciliogenesis arrested at stage 1, preventing axoneme elongation (Thiel et al. 2011).
Allele frequency/population data: No specific gnomAD/population carrier-frequency figures for these specific pathogenic NEK1 alleles were identified in this search; NEK1 loss-of-function variants overall are not vanishingly rare in the population because they also confer risk (in monoallelic form) for a distinct, later-onset adult disease (see below), implying population-level heterozygote carriers of NEK1 LoF alleles exist at appreciable frequency, though homozygous/compound-heterozygous null combinations producing SRTD6 remain very rare.
Notable pleiotropy — NEK1 and ALS. NEK1 is independently one of the most robustly replicated ALS risk genes: heterozygous NEK1 loss-of-function variants are found in ~2–3% of both familial and sporadic amyotrophic lateral sclerosis cases (van Rheenen et al., Nat Genet 2016; Rifai et al. 2025, PMID:38986433). NEK1 is implicated in cilia formation, DNA-damage response, microtubule stability, and axonal polarity; the missense variant p.Arg261His has specifically been linked to increased ALS susceptibility, and NEK1 loss-of-function has been shown to induce DNA damage accumulation in ALS patient-derived motor neurons (Higelin et al. 2018, PMID:29929116) and to disrupt microtubule homeostasis/nuclear import (PMC10431718). This represents an important gene-dosage relationship for curation purposes: monoallelic NEK1 LoF → ALS susceptibility in adults; biallelic (or digenic NEK1+DYNC2H1) LoF → lethal perinatal skeletal ciliopathy (SRTD6).
Epigenetics/chromosomal abnormalities: No epigenetic mechanism or large chromosomal rearrangement mechanism has been described for SRTD6; it is a classical biallelic point-mutation/small-indel Mendelian disorder.
No environmental toxins, lifestyle factors, or infectious triggers are documented as contributing to SRTD6 — it is a fully genetically determined ciliopathy with no reported gene-environment modulation.
Molecular pathway: NEK1 is a NIMA-family serine/threonine kinase that localizes to the centrosome and basal body of the primary cilium and is required for the initiation and elongation of ciliogenesis. Together with its digenic partner DYNC2H1 (the motor subunit of cytoplasmic dynein-2, which drives retrograde intraflagellar transport, IFT), NEK1 loss disrupts both the assembly and the trafficking machinery of the primary cilium.
Causal chain (upstream → downstream): 1. Molecular trigger: Biallelic loss-of-function NEK1 variants (or digenic NEK1+DYNC2H1 haploinsufficiency) abolish or truncate functional NEK1 kinase. 2. Cellular process: Ciliogenesis is arrested at an early stage (stage 1 by EM), producing severely reduced cilium number and grossly abnormal (short, broad-based, thin-apex) cilium morphology in patient fibroblasts. 3. Tissue/organ process: Impaired Hedgehog and other cilium-dependent signaling in the growth plate disrupts endochondral ossification, producing shortened long bones, short ribs, and the constricted trident-shaped thoracic skeleton; impaired ciliary signaling in the kidney nephron produces cystic dilatation of tubules/glomeruli; impaired ciliary signaling during organogenesis produces situs/laterality-adjacent defects such as intestinal malrotation and congenital heart defects. 4. Organism-level outcome: The severely restricted thoracic cage causes pulmonary hypoplasia and, in the classic lethal presentation, fatal neonatal respiratory insufficiency.
Cell types/biological processes involved: - Chondrocytes and growth-plate cells (GO:0001501 skeletal system development; GO:0060173 limb development) — CL:0000138 chondrocyte - Ciliated epithelial cells across multiple organs (GO:0060271 cilium assembly; GO:0003341 cilium movement) - Renal tubular epithelial cells (CL:1000838 kidney collecting duct principal cell / general nephron epithelium) - Centrosome/basal body machinery (GO:0005929 cilium; GO:0005813 centrosome)
Protein dysfunction: NEK1 truncating/nonsense/splice variants are predicted to produce a nonfunctional or absent kinase; DYNC2H1 missense/compound-heterozygous variants impair motor-protein function within the IFT-B/dynein-2 retrograde transport complex.
Molecular profiling / advanced omics: No transcriptomic, proteomic, single-cell, or spatial-omics dataset specific to SRTD6/NEK1 patient tissue was identified in this search; the mechanistic evidence base rests on classic cellular/EM ciliary phenotyping in patient-derived fibroblasts (Thiel et al. 2011) rather than -omics profiling.
Organ level: - Primary: skeletal system (rib cage, long bones, pelvis/acetabulum), lungs (secondary hypoplasia) - Secondary/associated: kidneys (cystic dysplasia), liver, intestines (malrotation), heart, oral cavity (lingual/gingival hamartomas), craniofacial structures (cleft lip/palate) - Body systems: skeletal, respiratory, renal, hepatobiliary, gastrointestinal, cardiovascular
Tissue/cell level: Cartilage and growth-plate chondrocytes (endochondral bone), renal tubular/glomerular epithelium, ciliated epithelial cell populations broadly (UBERON:0000922 embryonic structures during organogenesis are relevant given the developmental timing).
Subcellular level: Primary cilium and basal body/centrosome (GO:0005929 cilium; GO:0036064 ciliary basal body; GO:0005813 centrosome) — the direct organelle-level site of NEK1/DYNC2H1 dysfunction.
Anatomical terms (UBERON): - UBERON:0002228 rib - UBERON:0002228 thoracic cage / UBERON:0000915 thoracic segment - UBERON:0002203 pelvic girdle / acetabulum - UBERON:0002113 kidney - UBERON:0002370 thymus (not specifically implicated but general organogenesis context) - UBERON:0002049 tibia
Laterality: No consistent lateralization pattern reported; skeletal changes are typically bilateral/symmetric, consistent with a systemic skeletal dysplasia rather than a focal or asymmetric process.
Epidemiology: No SRTD6-specific incidence figure was located; the short-rib thoracic dysplasia group as a whole (encompassing Jeune/asphyxiating thoracic dystrophy, the SRPS types, Mainzer-Saldino, and Ellis-van Creveld) is estimated at 1:100,000 to 1:130,000 live births (search summary citing SRTD group literature; consistent with Jeune-syndrome-specific figures at NORD). SRTD6/Majewski-type specifically is a small fraction of this pool — the discovery and follow-up cohorts each comprised only a handful to ~13-20 families.
Inheritance pattern: Autosomal recessive (biallelic NEK1), with documented digenic diallelic inheritance (heterozygous NEK1 + heterozygous DYNC2H1) as an alternative genetic architecture in some families — an important nuance beyond simple monogenic AR inheritance.
Penetrance/expressivity: The classic homozygous/compound-heterozygous null genotype appears fully penetrant for the lethal phenotype; variable expressivity is suggested by reports of milder/non-lethal overlap phenotypes (PMID:22876582), potentially reflecting hypomorphic alleles or digenic combinations with partial residual function.
Consanguinity: The founding genetic mapping studies used consanguineous families (homozygosity mapping design), consistent with an increased risk in consanguineous unions given the rare recessive allele frequency.
Founder effects/carrier frequency/geographic distribution: No specific founder mutation or population-enriched carrier frequency was identified for SRTD6-causing NEK1 alleles in this search.
Demographics: No sex ratio skew is reported (autosomal, not X-linked); affected individuals are, by definition, prenatal/neonatal in age given the classic lethal presentation.
Prenatal imaging: Second- and third-trimester ultrasound is the primary diagnostic modality — short/micromelic long bones, narrow thorax, polydactyly, and (in Majewski type specifically) disproportionately short/ovoid tibiae are characteristic findings (Tonni et al. 2014, PMID:24854045; prenatal case series ScienceDirect 2012).
Postnatal/autopsy radiography: Short horizontal ribs, "trident" acetabular roof, shortened tubular bones — the classic radiographic constellation defining the SRTD/SRPS group and distinguishing Majewski (type II) from Saldino-Noonan (type I), Verma-Naumoff (type III), and Beemer-Langer (type IV) by specific limb-bone morphology (particularly tibial involvement in Majewski type).
Histopathology: Chondral growth-plate histology and renal/hepatic histopathology have been characterized in autopsy/prenatal-diagnosis case series (Tonni et al. 2014, PMC2890924).
Genetic testing: - Single-gene NEK1 sequencing or NEK1+DYNC2H1 dual testing given documented digenic inheritance - Skeletal dysplasia/ciliopathy gene panels (which would include NEK1, DYNC2H1, and other SRTD genes — the field now recognizes ~25 genes across the skeletal ciliopathy spectrum) - Exome/genome sequencing, particularly valuable given genetic heterogeneity within SRP type II (only ~9/13 cases explained by NEK1 or DYNC2H1 in the largest published cohort) and the possibility of digenic combinations that single-gene panels might miss if not designed to flag compound findings across two genes - Chromosomal microarray/karyotype are not primary diagnostic tools here (this is not a copy-number or aneuploidy disorder)
Differential diagnosis: Other SRTD/SRPS subtypes (Saldino-Noonan/type I, Verma-Naumoff/type III, Beemer-Langer/type IV), Ellis-van Creveld syndrome, Jeune syndrome (asphyxiating thoracic dystrophy), Mainzer-Saldino syndrome, and other lethal skeletal dysplasias (e.g., thanatophoric dysplasia) presenting with narrow thorax and limb shortening on prenatal ultrasound — differentiation is largely radiographic (limb-bone pattern) plus molecular confirmation (MDPI 2022 differential-diagnosis case report).
Screening: No population-based newborn or carrier screening program specific to SRTD6 exists; detection is via targeted prenatal ultrasound in at-risk (e.g., consanguineous or previously affected) families, followed by confirmatory molecular testing.
Mortality: The classic (biallelic-null) SRTD6/Majewski-type presentation is lethal in the neonatal period, with death from respiratory insufficiency secondary to pulmonary hypoplasia driven by the severely restricted thoracic cage — consistent with SRP types 1–4 broadly being "lethal in the newborn period because of severe pulmonary hypoplasia and other associated anomalies."
Milder/overlap phenotypes: At least one report describes a short rib-polydactyly phenotype "overlapping both lethal and nonlethal types" (PMID:22876582), indicating that the digenic or hypomorphic-allele end of the spectrum may permit survival, analogous to surviving forms of the broader SRTD group (e.g., Jeune syndrome, where children can survive infancy but face chronic thoracic insufficiency and progressive renal/hepatic disease).
Prognostic factors: Genotype severity (complete null biallelic NEK1 vs. digenic/hypomorphic combinations) likely drives the lethal-vs-survivable distinction, though this has not been formally quantified in a genotype-phenotype correlation study for SRTD6 specifically.
There is no disease-modifying or curative therapy for SRTD6; management is supportive and, for survivors of the perinatal period (extrapolating from the broader Jeune-syndrome/SRTD survivor literature), centers on mechanical thoracic expansion.
NCIT:C15329 (Surgical Procedure); therapeutic modality: DEVICE.No naturally occurring SRTD6/Majewski-type ciliopathy has been reported in non-human species in this search; this appears to be a human-specific clinical entity in the veterinary/comparative literature reviewed.
Mouse model — Nek1^kat2J^ (the "kat" mouse, for kidney, anemia, testis phenotype): - A spontaneous Nek1-null mouse mutant (kat2J allele) is the principal genetic model connecting Nek1 loss to ciliopathy phenotypes. Nek1 localizes to centrosomes and the primary cilium in this model, and kat2J homozygous mice develop polycystic kidney disease: kidney development is aberrant early, prior to gross cyst appearance — cortical zones are thin, populated by immature glomeruli, with excessive apoptosis across several cell types; cysts subsequently form postnatally in Bowman's space and multiple tubular subtypes (PMC4422189; Springer 2014). - Nek1 expression in the embryonic kidney is most prominent in cells destined to become podocytes and proximal tubules. - This model is explicitly framed in the primary literature as modeling "the ciliopathy polycystic kidney disease caused by abnormal ciliary structure or signaling" and directly links Nek1 mutation to a human ciliopathy (short-rib polydactyly syndrome type Majewski). - Limitation: The kat2J mouse model's published phenotyping emphasizes the renal cystic phenotype rather than the full skeletal (short-rib/short-limb/polydactyly) phenotype defining human SRTD6 — i.e., it recapitulates the ciliopathy/renal-cystic component with apparent fidelity but the mouse literature reviewed here does not establish whether it reproduces the diagnostic skeletal dysplasia, representing an open human-model-fidelity question for the skeletal component specifically. No dedicated skeletal-phenotyping publication for kat2J mice was surfaced in this search. - Cellular models: Patient-derived dermal fibroblasts are the key human cellular model used to establish the ciliogenesis defect (severely reduced cilium number/length, arrested ciliogenesis at stage 1) — this is IN_VITRO evidence directly from affected individuals, distinct from the mouse model (Thiel et al. 2011). - No zebrafish, Drosophila, C. elegans, iPSC-derived, or organoid model specific to NEK1-related SRTD6 was identified in this search (note: zebrafish morpholino/CRISPR knockdown of nek1 has been used in some ciliopathy contexts more broadly, but a dedicated citation was not surfaced here and should be verified against primary literature before curation).
Suggested Cell Ontology/model terms: CL:0000057 (fibroblast, for the patient-fibroblast ciliogenesis assay); NCBITaxon:10090 (Mus musculus, for the kat2J model); NCBITaxon:9606 (Homo sapiens, for fibroblast studies).
| Category | Suggested term |
|---|---|
| Disease (MONDO) | MONDO:0009894 |
| Gene 1 (HGNC) | hgnc:7744 (NEK1) |
| Gene 2, digenic (HGNC) | hgnc:2794 (DYNC2H1) |
| Inheritance (HP) | HP:0000007 (Autosomal recessive); HP:0010984 (Digenic inheritance) — for the NEK1+DYNC2H1 combination |
| Phenotype | HP:0000774 (Narrow chest), HP:0000773 (Short ribs), HP:0100259 (Postaxial polydactyly), HP:0003026 (Trident acetabular roof), HP:0000113 (Polycystic kidney dysplasia), HP:0002566 (Intestinal malrotation), HP:0001627 (Abnormal heart morphology), HP:0000175 (Cleft palate) |
| GO Biological Process | GO:0060271 (cilium assembly), GO:0007049 (cell cycle), GO:0006302 (double-strand break repair) |
| GO Cellular Component | GO:0005929 (cilium), GO:0036064 (ciliary basal body), GO:0005813 (centrosome) |
| Cell Type (CL) | CL:0000138 (chondrocyte), CL:0000057 (fibroblast) |
| Anatomy (UBERON) | UBERON:0002228 (rib), UBERON:0002113 (kidney), UBERON:0002049 (tibia) |
| Treatment (NCIT) | NCIT:C15329 (Surgical Procedure — thoracic expansion/VEPTR), NCIT:C15240 (Genetic Counseling) |
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 14 |
| Resolved | 14 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 3 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 2 |
| References weighed for topical relevance | 14 |
| On topic | 5 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:21211617 (abstract only): "combined haploinsufficiency of cilia formation and intraflagellar transport (IFT)"PMID:22876582 (abstract only): "overlapping both lethal and nonlethal types"