LAMA5-Related Bent Bone Dysplasia

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive. The three affected siblings were compound heterozygous for two LAMA5 missense variants, each parent carried one, and an unaffected sibling carried only one. The family was nonconsanguineous.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Because all three affected siblings were compound heterozygotes for both mutations and each parent carried of one of the variants, the inheritance pattern was consistent with an autosomal recessive disorder."

States the segregation and the inheritance conclusion drawn from it.

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Discussions and Knowledge Gaps

3

Is LAMA5 established as the cause of a bent-bone dysplasia, or is the gene-disease relationship still limited by resting on one kindred with two SIFT-benign missense alleles?

KNOWLEDGE GAP OPEN bbds2_single_kindred_gene_disease_validity

Attached to

genetic#LAMA5

Everything known about this disorder comes from three siblings in one family. The functional case is strong — reduced LAMA5 protein in three patient tissue types, a concordant gene-edited line, and a coherent signaling pathway — but neither allele is a null, both are called benign by at least one predictor, and no second family has been reported in the five years since. A second unrelated kindred, or a ClinGen Gene-Disease Validity assertion, would settle it. The ISDS committee listed the disorder in 2023 on this evidence, which is itself an expert judgement worth recording.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"We identified three siblings from a single nonconsanguineous family (International Skeletal Dysplasia Registry reference number R03–206) with skeletal defects that did not phenotypically or radiographically match any of the currently classified skeletal disorders."

Establishes that the entire case series is one sibship, which is the limitation this gap records.

Does the reduced canonical WNT signaling actually cause the under-mineralization in this disorder, or is it a parallel consequence of FYN loss that happens to be measurable?

KNOWLEDGE GAP OPEN bbds2_wnt_to_mineralization_step_unproven

Attached to

pathophysiology#Diminished Canonical WNT Signaling

The WNT node was investigated because under-mineralization was seen radiographically and WNT is known to drive mineralization — the reasoning runs from phenotype to candidate pathway. What was then measured is reduced TCF/LEF reporter activity and reduced LRP6 phosphorylation in chondrocytes and HeLa cells, which establishes that WNT output falls but not that this fall produces the bone phenotype. No rescue of mineralization by restoring WNT, and no skeletal model of Lama5 deficiency, is reported.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Based on the radiographic phenotype that included decreased mineralization of the axial and appendicular bone, we investigated whether altered WNT signaling could contribute to the phenotype since loss of WNT signaling negatively impacts skeletal mineralization"

Shows the investigation ran from the observed phenotype to the candidate pathway, which is why the causal direction is not established by the measurements that followed.

How much of the long-bone angulation is cell-autonomous to cartilage and bone, and how much is secondary to abnormal muscle function acting on a developing skeleton?

KNOWLEDGE GAP OPEN bbds2_muscle_contribution_to_bone_bending

Attached to

pathophysiology#Disordered Chondrogenesis and Skeletal Mineralization

LAMA5 is expressed in muscle as well as cartilage and bone, the affected siblings had arthrogryposis, elbow fusions and no respiratory effort at birth, and altered mechanical force during development is an established route to bone bending. If the mechanical contribution is substantial, the disorder is partly a neuromuscular one and the pathograph as curated understates that arm. No muscle histology or function data are reported.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Thus, the potential for abnormal muscular function due to loss of LAMA5 is of particular interest in this disorder since muscle defects have also been speculated to contribute to bending of appendicular bones by altered mechanical forces during development"

The authors raise the mechanical hypothesis and mark it as speculative, which is exactly the open question recorded here.

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Pathophysiology

5

Biallelic LAMA5 Missense Variants Destabilize Laminin Alpha-5

Two compound-heterozygous LAMA5 missense alleles, c.4213G>A (p.Ala1405Thr) and c.6157C>T (p.Arg2053Cys), sit in or beside the central EGF-like domains where disulfide bonding governs folding and secretion of the mature protein. The consequence is quantitative rather than qualitative: LAMA5 protein is significantly reduced in patient chondrocytes, fibroblasts and cartilage. This measured protein loss, not in-silico prediction, is what establishes pathogenicity — both variants are called benign by SIFT.

LAMA5 hgnc:6485

Genetic context allele_type: MISSENSE variant_origin: GERMLINE allelic_hit_role: BIALLELIC_INACTIVATION zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Compound heterozygosity for two germline LAMA5 missense alleles, each inherited from one unaffected parent. Curated as partial rather than complete loss of function because the mechanism is destabilization with residual protein, not a null.

extracellular matrix structural constituent GO:0005201 ↓ DECREASED

Downstream

Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure

Show evidence (3 references)

PMID:33242826 SUPPORT Human Clinical

"This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein."

Establishes LAMA5 as the causal gene for this bent-bone dysplasia.

PMID:33242826 SUPPORT In Vitro

"At the protein level, studies using primary chondrocytes, fibroblasts and cartilage derived from one of the affected individuals (R03-206G), showed statistically significantly decreased levels of LAMA5, demonstrating that the mutations in LAMA5 destabilized the protein"

Direct patient-tissue measurement that the alleles reduce LAMA5 protein, which is the mechanism this node asserts.

PMID:33242826 SUPPORT Computational

"Both mutations affected the protein in or near EGF-like domains involved in disulfide bonding, which are essential for proper folding and secretion of the mature protein"

Structural rationale for why missense changes at these positions destabilize rather than merely alter the protein.

Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure

Reduced alpha-5 laminin in the basement membrane leaves beta-1 integrin without its ligand, and the focal adhesion complex fails — but not by the textbook route. Phosphorylated FAK, the canonical integrin transducer, is unchanged in both patient chondrocytes and the hypomorphic cell line. What falls instead is PYK2, the FAK paralogue whose expression is largely confined to bone and cartilage, together with the skeletally enriched SRC-family kinase FYN and the downstream phospho-p130CAS and phospho-paxillin. The unchanged FAK is the load-bearing negative result: it is what makes this a distinct, tissue-restricted signaling axis rather than generic integrin failure, and it is why the disorder is skeletal despite LAMA5 being expressed almost everywhere.

chondrocyte CL:0000138

cell-matrix adhesion GO:0007160 ↓ DECREASED integrin-mediated signaling pathway GO:0007229 ↓ DECREASED focal adhesion assembly GO:0048041 ↓ DECREASED

Experimental models

HeLa LAMA5Hyp/Hyp gene-edited hypomorphic cell line CELL LINE Independently reproduces the full signaling signature seen in patient chondrocytes — reduced mature beta-1 integrin, reduced total and phosphorylated PYK2, reduced FYN, reduced phospho-p130CAS and phospho-paxillin, with FAK phosphorylation unchanged.

Downstream

Cytoskeletal Disorganization and Impaired Cell Adhesion

Diminished Canonical WNT Signaling

Show evidence (3 references)

PMID:33242826 SUPPORT In Vitro

"Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN."

Names the noncanonical axis this node represents.

PMID:33242826 SUPPORT In Vitro

"Although protein levels of the β1-integrin receptors were altered in defective LAMA5 cells, levels of phosphorylated FAK were not altered in either patient chondrocytes or LAMA5Hyp/Hyp cells"

The negative result that establishes the pathway is noncanonical: the usual integrin transducer is untouched.

PMID:33242826 SUPPORT In Vitro

"Relative to controls, both phosphorylated and total PYK2 levels were decreased in bent bone LAMA5 and HeLa LAMA5Hyp/Hyp mutant cells"

Quantifies the PYK2 arm in patient cells and in an independent gene-edited line.

Cytoskeletal Disorganization and Impaired Cell Adhesion

With the focal adhesion complex unassembled, the actin cytoskeleton is disorganized and vinculin — present at normal total levels — fails to localize into focal adhesions. The functional consequence measured is slower wound closure with no change in proliferation or survival, so this is an adhesion and migration defect rather than a growth defect.

actin cytoskeleton organization GO:0030036 ↓ DECREASED

Downstream

Disordered Chondrogenesis and Skeletal Mineralization

Show evidence (2 references)

PMID:33242826 SUPPORT In Vitro

"Actin staining showed a disorganized cytoskeleton and there was a reduced number of VCL focal adhesions in LAMA5Hyp/Hyp cells"

Direct imaging readout of the cytoskeletal and vinculin defect.

PMID:33242826 SUPPORT In Vitro

"These results confirmed a disruption in cellular focal adhesion properties in LAMA5 defective cells by altered cytoskeletal architecture, vinculin localization, and diminished cell healing."

The authors' summary of the adhesion phenotype, including that healing rather than proliferation is what is impaired.

Diminished Canonical WNT Signaling

SRC-family kinases including FYN act on the WNT co-receptor LRP6, so the kinase losses above propagate into WNT. Patient chondrocytes and the hypomorphic line both show reduced TCF/LEF reporter activity and reduced LRP6 Ser1490 phosphorylation after WNT3A. This is the node the authors reach for to explain the under-mineralization, since loss of WNT signaling depresses skeletal mineralization; the causal step from WNT to the radiographic phenotype is argued rather than demonstrated in this system.

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Downstream

Disordered Chondrogenesis and Skeletal Mineralization

Show evidence (2 references)

PMID:33242826 SUPPORT In Vitro

"Both patient chondrocytes and LAMA5Hyp/Hyp cells showed decreased TCF/LEF promoter activity"

Reporter-level readout of reduced canonical WNT output in two independent systems.

PMID:33242826 SUPPORT In Vitro

"These results indicate that defective expression of LAMA5 diminished activation of the WNT pathway likely through decreased active Src and FYN kinases."

Connects the WNT defect back to the kinase losses in the preceding node. The word "likely" marks it as the authors' inference.

Disordered Chondrogenesis and Skeletal Mineralization

LAMA5 is expressed throughout cartilage — growth plate, articular chondrocytes, perichondrium — as well as in periosteum, trabecular bone, ligament and muscle, and PYK2 and FYN share that distribution. Losing the adhesion axis in those tissues yields under-mineralized, sharply angulated long bones with abnormal cortices, an under-mineralized calvarium, platyspondyly with coronal clefts and hypoplastic acetabula. The paper also raises a mechanical contribution: the contractures and elbow fusions imply abnormal muscle function, and altered mechanical force during development is an established route to bone bending.

chondrocyte CL:0000138 osteoblast CL:0000062

skeletal system development GO:0001501 ↓ DECREASED biomineral tissue development GO:0031214 ↓ DECREASED

Downstream

Bowing of the Long Bones

Decreased Calvarial Ossification

Reduced Bone Mineral Density

Platyspondyly

Coronal Cleft Vertebrae

Hypoplastic Acetabulae

Congenital Hip Dislocation

Arthrogryposis Multiplex Congenita

Talipes Equinovarus

Elbow Dislocation

Respiratory Failure

Show evidence (3 references)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

The full radiographic phenotype this node produces.

PMID:33242826 SUPPORT In Vitro

"Our immunohistochemistry findings expand on the role of LAMA5 expression in musculoskeletal development beyond the previously described Type E capillaries, with expression in blood vessels in cartilage and ligament and expression in muscle, ligaments, periosteum, trabecular bone and throughout..."

Establishes that LAMA5 is present in the tissues whose development fails, which is what licenses a tissue-autonomous reading of this node.

PMID:33242826 SUPPORT Human Clinical

"This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."

Records the proposed mechanical/muscular contribution, hedged as "likely" by the authors and so curated as partial support.

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Pathograph

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

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Phenotypes

18

Cardiovascular 1

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists atrial septal defects among the clinical findings.

Ear 1

Abnormal Pinna Morphology HP:0000377

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"There were facial dysmorphisms, abnormally formed ears with tags, wide-spaced nipples, and atrial septal defects, among other findings (Table S1)."

Reports abnormally formed ears with tags.

Eye 1

Proptosis HP:0000520

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists proptosis among the clinical findings.

Head and Neck 2

Relative Macrocephaly HP:0004482

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists relative macrocephaly among the clinical findings.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists micrognathia among the clinical findings.

Limbs 3

Bowing of the Long Bones VERY_FREQUENT HP:0006487

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports bent long bones with mid-diaphyseal angulation, most marked in the femora.

Congenital Hip Dislocation HP:0001374

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports femoral head dislocation.

Talipes Equinovarus HP:0001762

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."

Reports bilateral talipes equinovarus.

Musculoskeletal 3

Reduced Bone Mineral Density HP:0004349

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Based on the radiographic phenotype that included decreased mineralization of the axial and appendicular bone, we investigated whether altered WNT signaling could contribute to the phenotype since loss of WNT signaling negatively impacts skeletal mineralization"

States decreased mineralization of both axial and appendicular bone as the observed radiographic phenotype.

Platyspondyly HP:0000926

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports platyspondyly.

Coronal Cleft Vertebrae HP:0003417

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports coronal clefts of the vertebrae.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Additionally, there was significant polyhydramnios in the prenatal period suggesting placental dysfunction or fetal inability to swallow properly."

Reports significant prenatal polyhydramnios.

Respiratory 1

Respiratory Failure VERY_FREQUENT HP:0002878

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."

Reports the respiratory cause of death and explicitly rules out a small chest as its explanation.

Other 5

Decreased Calvarial Ossification HP:0005474

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports under-mineralization of the calvarium.

Hypoplastic Acetabulae HP:0003274

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular..."

Reports hypoplastic acetabular roofs.

Elbow Dislocation HP:0003042

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists elbow dislocations among the clinical findings.

Arthrogryposis Multiplex Congenita VERY_FREQUENT HP:0002804

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."

Names arthrogryposis multiplex congenita as part of the phenotype.

Wide Intermamillary Distance HP:0006610

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."

Lists widely spaced nipples among the clinical findings.

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Genetic Associations

1

LAMA5

Gene: LAMA5 hgnc:6485 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:33242826 SUPPORT Human Clinical

"We identified biallelic mutations in LAMA5 that resulted in decreased Laminin α5 protein and produced a previously undescribed recessively inherited bent bone skeletal dysplasia."

The authors' summary statement of the gene-disease relationship.

PMID:33242826 SUPPORT Human Clinical

"These reports illustrate the potential for defective LAMA5 to produce disease, though the phenotypes differ from each other and our findings."

The authors' own assessment of the two prior human LAMA5 reports: they support the gene being disease-capable but describe different phenotypes, so they do not add cases to this entity.

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Medical Actions

2

Perinatal Palliative and Supportive Care

Action: Supportive Care NCIT:C15747

No disease-modifying therapy exists, and no treatment has been reported for this disorder. All three published individuals died shortly after birth of pulmonary insufficiency, so management is perinatal supportive and palliative care. This is recorded as the current standard of care by default, not as an evaluated intervention.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."

Establishes the perinatal-lethal course that determines the palliative framing; no therapeutic intervention is reported anywhere in the source.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal recessive recurrence risk of 25%. The delineating family had three affected and one unaffected child, so recurrence in this disorder is not theoretical. Both parental carrier states were established by sequencing, making targeted carrier and prenatal testing straightforward once the family alleles are known.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Because all three affected siblings were compound heterozygotes for both mutations and each parent carried of one of the variants, the inheritance pattern was consistent with an autosomal recessive disorder."

Establishes the recessive inheritance and the parental carrier states that the recurrence-risk counseling rests on.

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Progression

2

Prenatal

Age: Second and third trimester

Significant polyhydramnios in the prenatal period. All three affected siblings were delivered at term.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"Additionally, there was significant polyhydramnios in the prenatal period suggesting placental dysfunction or fetal inability to swallow properly."

Documents the prenatal course.

Perinatal lethality

Age: Birth to days

All three affected siblings died shortly after birth of presumed pulmonary insufficiency, despite normally sized chests. No survivor has been reported, so there is no postnatal natural history to record. Curated under `progression` rather than as a `phenotypes` entry because the HPO death terms sit in the Mortality/Aging branch rather than under HP:0000118 phenotypic abnormality, and so fall outside the PhenotypeTerm dynamic enum.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."

Records the perinatal outcome for the entire published series.

📊

Prevalence

1

Worldwide, published-case literature

Cases In Literature Ultra Rare

Three affected individuals, all siblings in a single nonconsanguineous family (International Skeletal Dysplasia Registry R03-206). No further family has been reported since the 2020 delineation, and no population-based estimate exists.

Show evidence (1 reference)

PMID:33242826 SUPPORT Human Clinical

"We identified three siblings from a single nonconsanguineous family (International Skeletal Dysplasia Registry reference number R03–206) with skeletal defects that did not phenotypically or radiographically match any of the currently classified skeletal disorders."

Establishes the size and structure of the entire published case series.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from LAMA5-Related Bent Bone Dysplasia:

Campomelic dysplasia (SOX9) MONDO:0007251

Overlapping Features The commonest perinatally lethal bent-bone dysplasia and therefore the first differential for angulated femora at term. Campomelic dysplasia is dominant and de novo, and adds Pierre-Robin sequence, hypoplastic scapulae, missing thoracic vertebral pedicles and 46,XY sex reversal, none of which are features of BBDS2.

Distinguishing Features

Causal gene SOX9 rather than LAMA5
Dominant de novo rather than autosomal recessive
46,XY sex reversal
Hypoplastic scapulae

Osteogenesis imperfecta type II

Overlapping Features The other cause of bent, under-mineralized bones at term. Distinguished by multiple prenatal fractures with callus, beaded ribs and a markedly small chest — the LAMA5 siblings had bent bones without that fracture burden, and the paper explicitly notes their chests were not small.

Distinguishing Features

Multiple prenatal fractures with callus formation
Beaded ribs and small chest
Usually dominant de novo COL1A1/COL1A2 variants

🧫

Experimental Models

1

HeLa LAMA5Hyp/Hyp gene-edited hypomorphic cell line CELL_LINE

A gene-edited HeLa line carrying a homozygous single-nucleotide insertion (317insA) that causes alternative splicing in exon 2 and deletes 51 amino acids from the LAMA5 short arm. It reduces LAMA5 protein by 88%, matching the reduction measured in patient tissue, and was used to reproduce the signaling findings independently of the patient cells.

Organism

human NCBITaxon:9606

Cell source

IMMORTALIZED

Publication

PMID:33242826

Pathograph links

Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure recapitulates fidelity: moderate Independently reproduces the full signaling signature seen in patient chondrocytes — reduced mature beta-1 integrin, reduced total and phosphorylated PYK2, reduced FYN, reduced phospho-p130CAS and phospho-paxillin, with FAK phosphorylation unchanged.

Limitations: HeLa is a cervical adenocarcinoma line, not a chondrocyte, so it cannot speak to the tissue restriction that is the point of the PYK2/FYN axis; it was chosen for high LAMA5 expression, not skeletal relevance. The allele is also an engineered hypomorph, not either patient variant, so it models the quantitative loss of LAMA5 rather than the specific missense changes.

Readouts

Total and phosphorylated PYK2

Direction: DECREASED

Interpretation: Confirms the PYK2 arm of the axis in a system with no patient genetic background.

Show evidence (1 reference)

PMID:33242826 SUPPORT In Vitro

"Relative to controls, both phosphorylated and total PYK2 levels were decreased in bent bone LAMA5 and HeLa LAMA5Hyp/Hyp mutant cells"

Reports the PYK2 measurement in the edited line alongside patient cells.

Wound-healing closure rate at 24 h

Direction: DECREASED

Interpretation: Functional confirmation that the adhesion defect changes cell behaviour, not only protein levels.

Show evidence (1 reference)

PMID:33242826 SUPPORT In Vitro

"The assay showed a reduced rate of healing by 10.8% in cells with deficient LAMA5 compared to control cells (92.8 ± 1.6% vs. 82.8 ± 2.2%; p = 0.0013), indicating diminished adhesion properties"

Quantifies the migration deficit with an explicit p value.

Show evidence (1 reference)

PMID:33242826 SUPPORT In Vitro

"The mutation is a hypomorphic allele (LAMA5Hyp) which in the homozygous state reduced LAMA5 protein by 88% (Fig. 4B-D), similar to the levels found in the patient-derived tissues with biallelic LAMA5 mutations."

Establishes that the model reproduces the degree of LAMA5 loss seen in patients, which is what makes it informative for the signaling node.

{ }

Source YAML

click to show

name: LAMA5-Related Bent Bone Dysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
synonyms:
- BBDS2
- Bent Bone Dysplasia Syndrome 2
- bent bone dysplasia, LAMA5-related
- LAMA5-related bent bone dysplasia
- laminin alpha-5-related bent bone dysplasia
description: >-
  Bent bone dysplasia syndrome 2 (BBDS2) is an ultra-rare, perinatally lethal
  bent-bone skeletal dysplasia caused by biallelic LAMA5 variants that
  destabilize laminin alpha-5, a major basement-membrane protein. It was
  delineated in three siblings whose phenotype matched no classified skeletal
  disorder: sharply angulated, under-mineralized femora, an under-mineralized
  calvarium, platyspondyly with coronal clefts, hypoplastic acetabular roofs
  with femoral head dislocation, and severe distal limb contractures, together
  with facial dysmorphism, ear anomalies and atrial septal defects. All three
  died shortly after birth of pulmonary insufficiency despite a normally sized
  chest.

  The interest of the entry is the mechanism. Every other bent-bone dysplasia
  works through a transcription factor (SOX9), a cytokine receptor (LIFR,
  IL6ST), a growth-factor receptor (FGFR2) or a motor/matricellular protein
  (KIF5B, CCN2). BBDS2 works through the basement membrane itself, and through
  a focal-adhesion route that is explicitly *not* the canonical one: FAK
  phosphorylation is unchanged in patient chondrocytes, while the paralogous
  kinase PYK2 — whose expression is largely restricted to bone and cartilage —
  and the skeletally enriched SRC-family kinase FYN are both reduced. The
  authors name the resulting axis LAMA5–beta1 integrin–PYK2–FYN, and trace it
  onward to a disorganized actin cytoskeleton, fewer vinculin focal adhesions,
  reduced cell migration and blunted canonical WNT signaling, which is the
  plausible link to the under-mineralization.

  Both LAMA5 alleles are missense changes in or near the central EGF-like
  domains, where disulfide bonding governs folding and secretion; each is
  individually benign by SIFT and each parent carries one without phenotype.
  The evidence that they are pathogenic is not in silico prediction but the
  measured loss of LAMA5 protein in patient chondrocytes, fibroblasts and
  cartilage, reproduced in a gene-edited hypomorphic cell line that
  independently gives the same signaling defects.
disease_term:
  preferred_term: bent bone dysplasia syndrome 2
  term:
    id: MONDO:0859573
    label: bent bone dysplasia syndrome 2
parents:
- hereditary disease
- Skeletal Dysplasia
notes: >-
  NAMING: gene-anchored because "bent bone dysplasia syndrome" alone is
  locus-ambiguous — it names two diseases, FGFR2 and LAMA5. The OMIM/MONDO numbering
  (BBDS2) is kept as a synonym and as the `disease_term` label. Same rule as its FGFR2
  counterpart and as the two kyphomelic dysplasia entries in the same ISDS group.

  LUMP/SPLIT: this entry is deliberately separate from
  kb/disorders/FGFR2-Related_Bent_Bone_Dysplasia.yaml (bent bone dysplasia syndrome
  1, FGFR2; MONDO:0013815; OMIM:614592). The two share a name and a
  radiographic sign and nothing else: BBDS1 is dominant and de novo, BBDS2 is
  recessive; BBDS1 is a receptor-trafficking and ribosome-biogenesis disorder of
  the osteoprogenitor, BBDS2 is a basement-membrane and focal-adhesion disorder
  of the chondrocyte. OMIM, MONDO and the ISDS 2023 nosology all list them
  separately (NOS 20-0050 and NOS 20-0060), and merging them would put two
  unrelated mechanisms behind one pathograph.

  The evidence base is one family. Three affected siblings, both parents and one
  unaffected sibling were sequenced and the segregation is complete, and the
  protein-level and cell-line work is substantial — but no second family has
  been reported, and the ISDS 2023 row carries no MIM number for the disorder
  (OMIM:620076 was minted subsequently). Claims here are therefore scoped to
  that kindred rather than stated as the disease's general natural history.

  Two earlier human LAMA5 reports describe different phenotypes — a
  heterozygous p.Val3140Met with skin, muscle and joint findings that was also
  present in unaffected relatives, and a homozygous p.Arg2659Trp in presynaptic
  myasthenic syndrome in an individual who also carried a homozygous LAMA1
  variant. Neither is a bent-bone dysplasia and neither is curated here. Note
  also that biallelic LAMA5 variants cause congenital/infantile nephrotic
  syndrome, which the ISDS table flags on this row; that is a separate
  phenotype and is not curated as part of this entry.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian recessive skeletal dysplasia (ISDS bent-bone group). The
      perinatal pulmonary insufficiency and the atrial septal defects are
      curated as phenotypes of the single LAMA5 disorder rather than as
      additional Harrison's Parts.
  isds_skeletal_category:
  - classification_value: bent_bone_dysplasia
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (11th edition;
      Unger et al., PMID:36779427), group 20 "Bent bones dysplasia group",
      entry NOS 20-0060, listed there as "Bent bone dysplasia, LAMA5-related"
      (AR, LAMA5). This is the only group-20 row with no MIM number in the 2023
      table — OMIM:620076 (BBDS2) was minted after the revision — and the
      committee attaches the comment that biallelic LAMA5 variants are also
      associated with congenital or infantile nephrotic syndrome. The
      IL6ST-related and LAMA5-related rows are both new in 2023; neither has a
      counterpart in the 2019 revision (PMID:31633310).
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive. The three affected siblings were compound
    heterozygous for two LAMA5 missense variants, each parent carried one, and
    an unaffected sibling carried only one. The family was nonconsanguineous.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because all three affected siblings were compound heterozygotes for both mutations and each parent carried of one of the variants, the inheritance pattern was consistent with an autosomal recessive disorder."
    explanation: >-
      States the segregation and the inheritance conclusion drawn from it.
prevalence:
- population: Worldwide, published-case literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three affected individuals, all siblings in a single nonconsanguineous
    family (International Skeletal Dysplasia Registry R03-206). No further
    family has been reported since the 2020 delineation, and no population-based
    estimate exists.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three siblings from a single nonconsanguineous family (International Skeletal Dysplasia Registry reference number R03–206) with skeletal defects that did not phenotypically or radiographically match any of the currently classified skeletal disorders."
    explanation: >-
      Establishes the size and structure of the entire published case series.
pathophysiology:
- name: Biallelic LAMA5 Missense Variants Destabilize Laminin Alpha-5
  biological_scale: MOLECULAR
  description: >-
    Two compound-heterozygous LAMA5 missense alleles, c.4213G>A (p.Ala1405Thr)
    and c.6157C>T (p.Arg2053Cys), sit in or beside the central EGF-like domains
    where disulfide bonding governs folding and secretion of the mature protein.
    The consequence is quantitative rather than qualitative: LAMA5 protein is
    significantly reduced in patient chondrocytes, fibroblasts and cartilage.
    This measured protein loss, not in-silico prediction, is what establishes
    pathogenicity — both variants are called benign by SIFT.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    allelic_hit_role: BIALLELIC_INACTIVATION
    zygosity: COMPOUND_HETEROZYGOUS
    allele_type: MISSENSE
    description: >-
      Compound heterozygosity for two germline LAMA5 missense alleles, each
      inherited from one unaffected parent. Curated as partial rather than
      complete loss of function because the mechanism is destabilization with
      residual protein, not a null.
  genes:
  - preferred_term: LAMA5
    term:
      id: hgnc:6485
      label: LAMA5
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: DECREASED
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein."
    explanation: >-
      Establishes LAMA5 as the causal gene for this bent-bone dysplasia.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "At the protein level, studies using primary chondrocytes, fibroblasts and cartilage derived from one of the affected individuals (R03-206G), showed statistically significantly decreased levels of LAMA5, demonstrating that the mutations in LAMA5 destabilized the protein"
    explanation: >-
      Direct patient-tissue measurement that the alleles reduce LAMA5 protein,
      which is the mechanism this node asserts.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Both mutations affected the protein in or near EGF-like domains involved in disulfide bonding, which are essential for proper folding and secretion of the mature protein"
    explanation: >-
      Structural rationale for why missense changes at these positions
      destabilize rather than merely alter the protein.
  downstream:
  - target: Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure
- name: Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure
  biological_scale: CELLULAR
  description: >-
    Reduced alpha-5 laminin in the basement membrane leaves beta-1 integrin
    without its ligand, and the focal adhesion complex fails — but not by the
    textbook route. Phosphorylated FAK, the canonical integrin transducer, is
    unchanged in both patient chondrocytes and the hypomorphic cell line. What
    falls instead is PYK2, the FAK paralogue whose expression is largely
    confined to bone and cartilage, together with the skeletally enriched
    SRC-family kinase FYN and the downstream phospho-p130CAS and
    phospho-paxillin. The unchanged FAK is the load-bearing negative result: it
    is what makes this a distinct, tissue-restricted signaling axis rather than
    generic integrin failure, and it is why the disorder is skeletal despite
    LAMA5 being expressed almost everywhere.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: cell-matrix adhesion
    term:
      id: GO:0007160
      label: cell-matrix adhesion
    modifier: DECREASED
  - preferred_term: integrin-mediated signaling pathway
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: focal adhesion assembly
    term:
      id: GO:0048041
      label: focal adhesion assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN."
    explanation: >-
      Names the noncanonical axis this node represents.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although protein levels of the β1-integrin receptors were altered in defective LAMA5 cells, levels of phosphorylated FAK were not altered in either patient chondrocytes or LAMA5Hyp/Hyp cells"
    explanation: >-
      The negative result that establishes the pathway is noncanonical: the
      usual integrin transducer is untouched.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Relative to controls, both phosphorylated and total PYK2 levels were decreased in bent bone LAMA5 and HeLa LAMA5Hyp/Hyp mutant cells"
    explanation: >-
      Quantifies the PYK2 arm in patient cells and in an independent
      gene-edited line.
  downstream:
  - target: Cytoskeletal Disorganization and Impaired Cell Adhesion
  - target: Diminished Canonical WNT Signaling
- name: Cytoskeletal Disorganization and Impaired Cell Adhesion
  biological_scale: CELLULAR
  description: >-
    With the focal adhesion complex unassembled, the actin cytoskeleton is
    disorganized and vinculin — present at normal total levels — fails to
    localize into focal adhesions. The functional consequence measured is
    slower wound closure with no change in proliferation or survival, so this
    is an adhesion and migration defect rather than a growth defect.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DECREASED
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Actin staining showed a disorganized cytoskeleton and there was a reduced number of VCL focal adhesions in LAMA5Hyp/Hyp cells"
    explanation: >-
      Direct imaging readout of the cytoskeletal and vinculin defect.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results confirmed a disruption in cellular focal adhesion properties in LAMA5 defective cells by altered cytoskeletal architecture, vinculin localization, and diminished cell healing."
    explanation: >-
      The authors' summary of the adhesion phenotype, including that healing
      rather than proliferation is what is impaired.
  downstream:
  - target: Disordered Chondrogenesis and Skeletal Mineralization
- name: Diminished Canonical WNT Signaling
  biological_scale: CELLULAR
  description: >-
    SRC-family kinases including FYN act on the WNT co-receptor LRP6, so the
    kinase losses above propagate into WNT. Patient chondrocytes and the
    hypomorphic line both show reduced TCF/LEF reporter activity and reduced
    LRP6 Ser1490 phosphorylation after WNT3A. This is the node the authors
    reach for to explain the under-mineralization, since loss of WNT signaling
    depresses skeletal mineralization; the causal step from WNT to the
    radiographic phenotype is argued rather than demonstrated in this system.
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both patient chondrocytes and LAMA5Hyp/Hyp cells showed decreased TCF/LEF promoter activity"
    explanation: >-
      Reporter-level readout of reduced canonical WNT output in two independent
      systems.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that defective expression of LAMA5 diminished activation of the WNT pathway likely through decreased active Src and FYN kinases."
    explanation: >-
      Connects the WNT defect back to the kinase losses in the preceding node.
      The word "likely" marks it as the authors' inference.
  downstream:
  - target: Disordered Chondrogenesis and Skeletal Mineralization
- name: Disordered Chondrogenesis and Skeletal Mineralization
  biological_scale: TISSUE
  description: >-
    LAMA5 is expressed throughout cartilage — growth plate, articular
    chondrocytes, perichondrium — as well as in periosteum, trabecular bone,
    ligament and muscle, and PYK2 and FYN share that distribution. Losing the
    adhesion axis in those tissues yields under-mineralized, sharply angulated
    long bones with abnormal cortices, an under-mineralized calvarium,
    platyspondyly with coronal clefts and hypoplastic acetabula. The paper also
    raises a mechanical contribution: the contractures and elbow fusions imply
    abnormal muscle function, and altered mechanical force during development is
    an established route to bone bending.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: DECREASED
  - preferred_term: biomineral tissue development
    term:
      id: GO:0031214
      label: biomineral tissue development
    modifier: DECREASED
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      The full radiographic phenotype this node produces.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our immunohistochemistry findings expand on the role of LAMA5 expression in musculoskeletal development beyond the previously described Type E capillaries, with expression in blood vessels in cartilage and ligament and expression in muscle, ligaments, periosteum, trabecular bone and throughout the cartilage, particularly in the growth plate and articular chondrocytes."
    explanation: >-
      Establishes that LAMA5 is present in the tissues whose development fails,
      which is what licenses a tissue-autonomous reading of this node.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."
    explanation: >-
      Records the proposed mechanical/muscular contribution, hedged as "likely"
      by the authors and so curated as partial support.
  downstream:
  - target: Bowing of the Long Bones
  - target: Decreased Calvarial Ossification
  - target: Reduced Bone Mineral Density
  - target: Platyspondyly
  - target: Coronal Cleft Vertebrae
  - target: Hypoplastic Acetabulae
  - target: Congenital Hip Dislocation
  - target: Arthrogryposis Multiplex Congenita
  - target: Talipes Equinovarus
  - target: Elbow Dislocation
  - target: Respiratory Failure
phenotypes:
- name: Bowing of the Long Bones
  category: Skeletal
  description: >-
    Distinctly bent long bones, most severely the femora, with mid-diaphyseal
    angulation and abnormal cortices. This is the defining sign that places the
    disorder in the ISDS bent-bone group.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports bent long bones with mid-diaphyseal angulation, most marked in the
      femora.
- name: Decreased Calvarial Ossification
  category: Skeletal
  description: >-
    Under-mineralization of the calvarium, present in all three siblings.
  phenotype_term:
    preferred_term: Decreased calvarial ossification
    term:
      id: HP:0005474
      label: Decreased calvarial ossification
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports under-mineralization of the calvarium.
- name: Reduced Bone Mineral Density
  category: Skeletal
  description: >-
    The long bones as well as the calvarium are under-mineralized, which is the
    phenotype the diminished WNT signaling is invoked to explain.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the radiographic phenotype that included decreased mineralization of the axial and appendicular bone, we investigated whether altered WNT signaling could contribute to the phenotype since loss of WNT signaling negatively impacts skeletal mineralization"
    explanation: >-
      States decreased mineralization of both axial and appendicular bone as the
      observed radiographic phenotype.
- name: Platyspondyly
  category: Skeletal
  description: >-
    Flattened vertebral bodies on the skeletal survey.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports platyspondyly.
- name: Coronal Cleft Vertebrae
  category: Skeletal
  description: >-
    Coronal clefts of the vertebral bodies accompanying the platyspondyly.
  phenotype_term:
    preferred_term: Coronal cleft vertebrae
    term:
      id: HP:0003417
      label: Coronal cleft vertebrae
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports coronal clefts of the vertebrae.
- name: Hypoplastic Acetabulae
  category: Skeletal
  description: >-
    Hypoplastic acetabular roofs, described as aplastic in the illustrated
    sibling.
  phenotype_term:
    preferred_term: Hypoplastic acetabulae
    term:
      id: HP:0003274
      label: Hypoplastic acetabulae
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports hypoplastic acetabular roofs.
- name: Congenital Hip Dislocation
  category: Skeletal
  description: >-
    Femoral head dislocation accompanying the hypoplastic acetabular roofs.
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings included under-mineralization of the calvarium (Fig. 1a-b and S1), distinctly bent, under-mineralized long bones, particularly of the femora, with mid-diaphyseal angulation (Fig. 1c-e and S1), platyspondyly with coronal clefts (Fig. 1f-g and S1), hypoplastic acetabular roofs with femoral head dislocation, (Fig. 1e and S1), and bilateral upper and lower extremity contractures (Fig. 1h-j and S1)."
    explanation: >-
      Reports femoral head dislocation.
- name: Elbow Dislocation
  category: Skeletal
  description: >-
    Elbow dislocations, with elbow fusions also described, part of the joint
    involvement that suggests a muscular contribution to the phenotype.
  phenotype_term:
    preferred_term: Elbow dislocation
    term:
      id: HP:0003042
      label: Elbow dislocation
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists elbow dislocations among the clinical findings.
- name: Arthrogryposis Multiplex Congenita
  category: Musculoskeletal
  description: >-
    Severe distal limb contractures with ulnar flexion at the wrist, named as
    arthrogryposis multiplex congenita by the authors.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."
    explanation: >-
      Names arthrogryposis multiplex congenita as part of the phenotype.
- name: Talipes Equinovarus
  category: Skeletal
  description: >-
    Bilateral talipes equinovarus.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder also likely includes abnormalities in muscle function based on the presence of elbow fusions, ulnar flexion contractions at the wrist (arthrogryposis multiplex congenita), bilateral talipes equinovarus, and failure to mount a respiratory effort at birth."
    explanation: >-
      Reports bilateral talipes equinovarus.
- name: Respiratory Failure
  category: Respiratory
  description: >-
    Failure to mount a respiratory effort at birth, and death shortly after
    birth from presumed pulmonary insufficiency. Notably the chests were not
    small, so this is not the thoracic-restriction mechanism that kills in most
    perinatally lethal skeletal dysplasias.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."
    explanation: >-
      Reports the respiratory cause of death and explicitly rules out a small
      chest as its explanation.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: >-
    Atrial septal defects, an extraskeletal feature of this disorder.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists atrial septal defects among the clinical findings.
- name: Relative Macrocephaly
  category: Craniofacial
  description: >-
    Relative macrocephaly with an enlarged skull, alongside the poorly
    mineralized calvarium.
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists relative macrocephaly among the clinical findings.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia, part of the dysmorphic facies.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists micrognathia among the clinical findings.
- name: Proptosis
  category: Craniofacial
  description: >-
    Proptosis, part of the dysmorphic facies.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists proptosis among the clinical findings.
- name: Abnormal Pinna Morphology
  category: Craniofacial
  description: >-
    Abnormally formed ears with tags.
  phenotype_term:
    preferred_term: Abnormal pinna morphology
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were facial dysmorphisms, abnormally formed ears with tags, wide-spaced nipples, and atrial septal defects, among other findings (Table S1)."
    explanation: >-
      Reports abnormally formed ears with tags.
- name: Wide Intermamillary Distance
  category: Other
  description: >-
    Widely spaced nipples.
  phenotype_term:
    preferred_term: Wide intermamillary distance
    term:
      id: HP:0006610
      label: Wide intermamillary distance
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included atrial septal defects, relative macrocephaly, micrognathia, proptosis, ear abnormalities, widely spaced nipples, elbow dislocations, and severe distal limb contractures (Table S1)."
    explanation: >-
      Lists widely spaced nipples among the clinical findings.
- name: Polyhydramnios
  category: Prenatal
  description: >-
    Significant polyhydramnios in the prenatal period, attributed by the authors
    to placental dysfunction or impaired fetal swallowing.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, there was significant polyhydramnios in the prenatal period suggesting placental dysfunction or fetal inability to swallow properly."
    explanation: >-
      Reports significant prenatal polyhydramnios.
genetic:
- name: LAMA5
  gene_term:
    preferred_term: LAMA5
    term:
      id: hgnc:6485
      label: LAMA5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    LAMA5 encodes the alpha-5 laminin chain of the basement membrane. The two
    causal alleles in the delineating kindred are c.4213G>A (p.Ala1405Thr),
    inherited from the father and carried also by one unaffected sibling, and
    c.6157C>T (p.Arg2053Cys), inherited from the mother. Both are rare in gnomAD
    (allele frequencies 0.0006 and 0.0003) and neither has been seen homozygous.
    Both were called benign by SIFT, which is why the protein-level work in
    patient chondrocytes, fibroblasts and cartilage carries the pathogenicity
    argument rather than prediction.

    Gene-disease validity here rests on a single kindred plus functional work.
    No ClinGen Gene-Disease Validity assertion for LAMA5 and this phenotype was
    found. Two earlier LAMA5 reports describe unrelated phenotypes and do not
    contribute to this gene-disease relationship.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified biallelic mutations in LAMA5 that resulted in decreased Laminin α5 protein and produced a previously undescribed recessively inherited bent bone skeletal dysplasia."
    explanation: >-
      The authors' summary statement of the gene-disease relationship.
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These reports illustrate the potential for defective LAMA5 to produce disease, though the phenotypes differ from each other and our findings."
    explanation: >-
      The authors' own assessment of the two prior human LAMA5 reports: they
      support the gene being disease-capable but describe different phenotypes,
      so they do not add cases to this entity.
experimental_models:
- name: HeLa LAMA5Hyp/Hyp gene-edited hypomorphic cell line
  experimental_model_type: CELL_LINE
  cell_source: IMMORTALIZED
  description: >-
    A gene-edited HeLa line carrying a homozygous single-nucleotide insertion
    (317insA) that causes alternative splicing in exon 2 and deletes 51 amino
    acids from the LAMA5 short arm. It reduces LAMA5 protein by 88%, matching
    the reduction measured in patient tissue, and was used to reproduce the
    signaling findings independently of the patient cells.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33242826
  modeled_mechanisms:
  - target: Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Independently reproduces the full signaling signature seen in patient
      chondrocytes — reduced mature beta-1 integrin, reduced total and
      phosphorylated PYK2, reduced FYN, reduced phospho-p130CAS and
      phospho-paxillin, with FAK phosphorylation unchanged.
    limitations: >-
      HeLa is a cervical adenocarcinoma line, not a chondrocyte, so it cannot
      speak to the tissue restriction that is the point of the PYK2/FYN axis;
      it was chosen for high LAMA5 expression, not skeletal relevance. The
      allele is also an engineered hypomorph, not either patient variant, so it
      models the quantitative loss of LAMA5 rather than the specific missense
      changes.
    readouts:
    - name: Total and phosphorylated PYK2
      target: Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure
      direction: DECREASED
      interpretation: >-
        Confirms the PYK2 arm of the axis in a system with no patient genetic
        background.
      evidence:
      - reference: PMID:33242826
        reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Relative to controls, both phosphorylated and total PYK2 levels were decreased in bent bone LAMA5 and HeLa LAMA5Hyp/Hyp mutant cells"
        explanation: >-
          Reports the PYK2 measurement in the edited line alongside patient
          cells.
    - name: Wound-healing closure rate at 24 h
      target: Noncanonical Beta-1 Integrin Focal Adhesion Signaling Failure
      direction: DECREASED
      interpretation: >-
        Functional confirmation that the adhesion defect changes cell behaviour,
        not only protein levels.
      evidence:
      - reference: PMID:33242826
        reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The assay showed a reduced rate of healing by 10.8% in cells with deficient LAMA5 compared to control cells (92.8 ± 1.6% vs. 82.8 ± 2.2%; p = 0.0013), indicating diminished adhesion properties"
        explanation: >-
          Quantifies the migration deficit with an explicit p value.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation is a hypomorphic allele (LAMA5Hyp) which in the homozygous state reduced LAMA5 protein by 88% (Fig. 4B-D), similar to the levels found in the patient-derived tissues with biallelic LAMA5 mutations."
    explanation: >-
      Establishes that the model reproduces the degree of LAMA5 loss seen in
      patients, which is what makes it informative for the signaling node.
progression:
- phase: Prenatal
  age_range: Second and third trimester
  notes: >-
    Significant polyhydramnios in the prenatal period. All three affected
    siblings were delivered at term.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, there was significant polyhydramnios in the prenatal period suggesting placental dysfunction or fetal inability to swallow properly."
    explanation: >-
      Documents the prenatal course.
- phase: Perinatal lethality
  age_range: Birth to days
  notes: >-
    All three affected siblings died shortly after birth of presumed pulmonary
    insufficiency, despite normally sized chests. No survivor has been reported,
    so there is no postnatal natural history to record. Curated under
    `progression` rather than as a `phenotypes` entry because the HPO death
    terms sit in the Mortality/Aging branch rather than under HP:0000118
    phenotypic abnormality, and so fall outside the PhenotypeTerm dynamic enum.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."
    explanation: >-
      Records the perinatal outcome for the entire published series.
treatments:
- name: Perinatal Palliative and Supportive Care
  description: >-
    No disease-modifying therapy exists, and no treatment has been reported for
    this disorder. All three published individuals died shortly after birth of
    pulmonary insufficiency, so management is perinatal supportive and
    palliative care. This is recorded as the current standard of care by
    default, not as an evaluated intervention.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals all delivered at term but died shortly after birth due to presumed pulmonary insufficiency, even though their chests were not small."
    explanation: >-
      Establishes the perinatal-lethal course that determines the palliative
      framing; no therapeutic intervention is reported anywhere in the source.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence risk of 25%. The delineating family had three
    affected and one unaffected child, so recurrence in this disorder is not
    theoretical. Both parental carrier states were established by sequencing,
    making targeted carrier and prenatal testing straightforward once the family
    alleles are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because all three affected siblings were compound heterozygotes for both mutations and each parent carried of one of the variants, the inheritance pattern was consistent with an autosomal recessive disorder."
    explanation: >-
      Establishes the recessive inheritance and the parental carrier states that
      the recurrence-risk counseling rests on.
differential_diagnoses:
- name: FGFR2-Related Bent Bone Dysplasia
  disease_term:
    preferred_term: bent bone dysplasia syndrome 1
    term:
      id: MONDO:0013815
      label: bent bone dysplasia syndrome 1
  description: >-
    The name-sharing differential, and radiographically the closest: both give
    bent long bones with a poorly mineralized calvarium in a perinatally lethal
    setting. BBDS1 is dominant and de novo rather than recessive, adds
    craniosynostosis, prenatal teeth and hypoplastic pubis and clavicles with a
    distinctive moustache-shaped clavicle and angel-shaped phalanges, and lacks
    the contractures, coronal clefts and atrial septal defects seen here.
  distinguishing_features:
  - Causal gene FGFR2 rather than LAMA5
  - Dominant de novo rather than autosomal recessive
  - Craniosynostosis and prenatal teeth
  - Moustache-shaped clavicles and angel-shaped phalanges
  notes: >-
    Both are in ISDS 2023 group 20 (NOS 20-0050 and NOS 20-0060). The shared
    "bent bone dysplasia syndrome" name reflects a shared radiographic sign, not
    a shared mechanism.
- name: Campomelic dysplasia (SOX9)
  disease_term:
    preferred_term: campomelic dysplasia
    term:
      id: MONDO:0007251
      label: campomelic dysplasia
  description: >-
    The commonest perinatally lethal bent-bone dysplasia and therefore the first
    differential for angulated femora at term. Campomelic dysplasia is dominant
    and de novo, and adds Pierre-Robin sequence, hypoplastic scapulae, missing
    thoracic vertebral pedicles and 46,XY sex reversal, none of which are
    features of BBDS2.
  distinguishing_features:
  - Causal gene SOX9 rather than LAMA5
  - Dominant de novo rather than autosomal recessive
  - 46,XY sex reversal
  - Hypoplastic scapulae
- name: Osteogenesis imperfecta type II
  description: >-
    The other cause of bent, under-mineralized bones at term. Distinguished by
    multiple prenatal fractures with callus, beaded ribs and a markedly small
    chest — the LAMA5 siblings had bent bones without that fracture burden, and
    the paper explicitly notes their chests were not small.
  distinguishing_features:
  - Multiple prenatal fractures with callus formation
  - Beaded ribs and small chest
  - Usually dominant de novo COL1A1/COL1A2 variants
  notes: >-
    The 2023 ISDS table footnote to group 20 makes this differential explicit:
    bent bones is an unspecific sign that also occurs in bone-fragility
    disorders, and the reader is sent to the OI group.
discussions:
- discussion_id: bbds2_single_kindred_gene_disease_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#LAMA5
  prompt: >-
    Is LAMA5 established as the cause of a bent-bone dysplasia, or is the
    gene-disease relationship still limited by resting on one kindred with two
    SIFT-benign missense alleles?
  rationale: >-
    Everything known about this disorder comes from three siblings in one
    family. The functional case is strong — reduced LAMA5 protein in three
    patient tissue types, a concordant gene-edited line, and a coherent
    signaling pathway — but neither allele is a null, both are called benign by
    at least one predictor, and no second family has been reported in the five
    years since. A second unrelated kindred, or a ClinGen Gene-Disease Validity
    assertion, would settle it. The ISDS committee listed the disorder in 2023
    on this evidence, which is itself an expert judgement worth recording.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three siblings from a single nonconsanguineous family (International Skeletal Dysplasia Registry reference number R03–206) with skeletal defects that did not phenotypically or radiographically match any of the currently classified skeletal disorders."
    explanation: >-
      Establishes that the entire case series is one sibship, which is the
      limitation this gap records.
- discussion_id: bbds2_wnt_to_mineralization_step_unproven
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Diminished Canonical WNT Signaling
  prompt: >-
    Does the reduced canonical WNT signaling actually cause the
    under-mineralization in this disorder, or is it a parallel consequence of
    FYN loss that happens to be measurable?
  rationale: >-
    The WNT node was investigated because under-mineralization was seen
    radiographically and WNT is known to drive mineralization — the reasoning
    runs from phenotype to candidate pathway. What was then measured is reduced
    TCF/LEF reporter activity and reduced LRP6 phosphorylation in chondrocytes
    and HeLa cells, which establishes that WNT output falls but not that this
    fall produces the bone phenotype. No rescue of mineralization by restoring
    WNT, and no skeletal model of Lama5 deficiency, is reported.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the radiographic phenotype that included decreased mineralization of the axial and appendicular bone, we investigated whether altered WNT signaling could contribute to the phenotype since loss of WNT signaling negatively impacts skeletal mineralization"
    explanation: >-
      Shows the investigation ran from the observed phenotype to the candidate
      pathway, which is why the causal direction is not established by the
      measurements that followed.
- discussion_id: bbds2_muscle_contribution_to_bone_bending
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disordered Chondrogenesis and Skeletal Mineralization
  prompt: >-
    How much of the long-bone angulation is cell-autonomous to cartilage and
    bone, and how much is secondary to abnormal muscle function acting on a
    developing skeleton?
  rationale: >-
    LAMA5 is expressed in muscle as well as cartilage and bone, the affected
    siblings had arthrogryposis, elbow fusions and no respiratory effort at
    birth, and altered mechanical force during development is an established
    route to bone bending. If the mechanical contribution is substantial, the
    disorder is partly a neuromuscular one and the pathograph as curated
    understates that arm. No muscle histology or function data are reported.
  evidence:
  - reference: PMID:33242826
    reference_title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, the potential for abnormal muscular function due to loss of LAMA5 is of particular interest in this disorder since muscle defects have also been speculated to contribute to bending of appendicular bones by altered mechanical forces during development"
    explanation: >-
      The authors raise the mechanical hypothesis and mark it as speculative,
      which is exactly the open question recorded here.
references:
- reference: PMID:33242826
  title: "Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."

📚

References & Deep Research

References

2

PMID:33242826

Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia.

No top-level findings curated for this source.

PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

LAMA5-Related Bent Bone Dysplasia

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