Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders

Rosa Neto, Nilton Salles; Pereira, Ivânio Alves; Sztajnbok, Flávio Roberto; Azevedo, Valderílio Feijó

doi:10.1186/s42358-024-00373-z

Nilton Salles Rosa Neto^**Correspondence: Nilton Salles Rosa Neto nsalles@yahoo.com

contributed equally to this manuscript

reviewed and approved the final version of the manuscript

Centro de Doenças Raras e da Imunidade, Hospital Nove de Julho, Rua Peixoto Gomide, 285, Cerqueira César, São Paulo CEP 01409-001, SP, Brazil

Universidade Santo Amaro, São Paulo, Brazil

https://orcid.org/0000-0001-8457-5132

Ivânio Alves Pereira

contributed equally to this manuscript

reviewed and approved the final version of the manuscript

Universidade do Sul de Santa Catarina, Florianópolis, Brazil

Flávio Roberto Sztajnbok

contributed equally to this manuscript

reviewed and approved the final version of the manuscript

Department of Pediatrics, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Valderílio Feijó Azevedo

contributed equally to this manuscript

reviewed and approved the final version of the manuscript

Department of Internal Medicine, Universidade Federal of Paraná, Curitiba, Brazil

*Correspondence: Nilton Salles Rosa Neto nsalles@yahoo.com

Collagen type	Alpha chain	Disease	OMIM condition [¹²12 Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {Accessed December 10th, 2023}. https://omim.org/. https://omim.org/... ]	Inheritance	2023 Skeletal dysplasia nosology [⁸8 Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–209. https://doi.org/10.1002/ajmg.a.63132. https://doi.org/10.1002/ajmg.a.63132... ]
Type 1	α1	Caffey disease	114000	AD	NOS 25-0030
		Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1	619115	AD
		Ehlers-Danlos syndrome, arthrochalasia type, 1	130060	AD
		Osteogenesis imperfecta, non-deforming	166200	AD	NOS 26-0010
		Osteogenesis imperfecta, severe perinatal	166210	AD	NOS 26-0030
		Osteogenesis imperfecta, progressively deforming	259420	AD	NOS 26-0080
		Osteogenesis imperfecta, moderate	166220	AD	NOS 26-0270
	α2	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2	619120	AD
		Ehlers-Danlos syndrome, arthrochalasia type, 2	617821	AD
		Ehlers-Danlos syndrome, cardiac valvular type	225320	AR
		Osteogenesis imperfecta, non-deforming	166200	AD	NOS 26-0020
		Osteogenesis imperfecta, severe perinatal	166210	AD	NOS 26-0040
		Osteogenesis imperfecta, progressively deforming	259420	AD	NOS 26-0090
		Osteogenesis imperfecta, moderate	166220	AD	NOS 26-0280
Type 2	α1	Achondrogenesis	200610	AD	NOS 02-0010
		Hypochondrogenesis	200610	AD	NOS 02-0020
		Dysplasia of the proximal femoral epiphyses (Avascular necrosis of the femoral head)	608805	AD	NOS 02-0100
		Spondyloepiphyseal dysplasia with metatarsal shortening (Czech dysplasia)	609162	AD	NOS 02-0080
		Kniest dysplasia	156550	AD	NOS 02-0060
		Dysplasia of the proximal femoral epiphyses (Legg-Calve-Perthes disease)	150600	AD	NOS 02-0100
		Spondyloepiphyseal dysplasia congenita (Osteoarthritis with mild chondrodysplasia)	604864	AD	NOS 02-0040
		Platyspondylic dysplasia, Torrance type	151210	AD	NOS 02-0030
		Spondyloepiphyseal dysplasia congenita	183900	AD	NOS 02-0040
		Spondylometaepiphyseal dysplasia, Strudwick type	184250	AD	NOS 02-0050
		Spondyloepiphyseal dysplasia, Stanescu type	616583	AD	NOS 02-0050
		Spondyloperipheral dysplasia	271700	AD	NOS 02-0070
		Stickler syndrome, type I	108300	AD	NOS 02-0090
		Stickler syndrome, type I, nonsyndromic ocular	609508	AD
Type 3	α1	Ehlers-Danlos syndrome, vascular type	130050	AD
		Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	618343	AR
Type 5	α1	Ehlers-Danlos syndrome, classic type, 1	130000	AD
		Fibromuscular dysplasia, multifocal	619329	AD
	α2	Ehlers-Danlos syndrome, classic type, 2	130010	AD
Type 9	α1	Stickler syndrome, type IV	614134	AR	NOS 09-0080
		Epiphyseal dysplasia, multiple	614135	AD	NOS 09-0050
	α2	Epiphyseal dysplasia, multiple	600204	AD	NOS 09-0060
		Stickler syndrome, type V	614284	AR	NOS 09-0090
	α3	Epiphyseal dysplasia, multiple	600969	AD	NOS 09-0070
		Stickler syndrome, type VI	120270	AR	NOS 09-0100
Type 10	α1	Metaphyseal chondrodysplasia, Schmid type	156500	AD	NOS 11-0010

Type 11	α1	Marshall syndrome	154780	AD	NOS 03-0020
		Stickler syndrome, type II	604841	AD	NOS 03-0010
	α2	Stickler syndrome, non-ocular type	184840	AD	NOS 03-0030
		Otospondylomegaepiphyseal dysplasia, autosomal dominant	184840	AD	NOS 03-0070
		Otospondylomegaepiphyseal dysplasia, autosomal recessive	215150	AR	NOS 03-0060
Type 27	α1	Steel syndrome	615155	AR	NOS 13-0300

OI Type	Inheritance	Previous classification	Current classification (2023 Skeletal dysplasia nosology) [⁸8 Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–209. https://doi.org/10.1002/ajmg.a.63132. https://doi.org/10.1002/ajmg.a.63132... ]	Gene	2023 Skeletal dysplasia nosology code [⁸8 Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–209. https://doi.org/10.1002/ajmg.a.63132. https://doi.org/10.1002/ajmg.a.63132... ]	OMIM condition [¹²12 Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {Accessed December 10th, 2023}. https://omim.org/. https://omim.org/... ]
Defects in collagen synthesis, structure, or processing
I	AD	Mild	Non-deforming	COL1A1	NOS26-0010	166200
			Non-deforming	COL1A2	NOS26-0020	166200
II	AD	Lethal	Severe perinatal	COL1A1	NOS26-0030	166210
			Severe perinatal	COL1A2	NOS26-0040	166210
III	AD	Progressive Deforming	Progressively deforming	COL1A1	NOS26-0080	259420
			Progressively deforming	COL1A2	NOS26-0090	259420
IV	AD	Moderate	Moderate	COL1A1	NOS26-0270	166220
			Moderate	COL1A2	NOS26-0280	166220
XIII	AR	Mild/Severe	Progressively deforming	BMP1	NOS26-0180	614856
Defects in bone mineralization
V	AR	Variable, Distinctive Histology	Progressively deforming	IFITM5	NOS26-0100	610967
			Moderate	IFITM5	NOS26-0300	166220
			OI With calcification of interosseous membranes and/or hypertrophic callus	IFITM5	NOS26-0350	610967
VI	AR	Moderate/Severe	Progressively deforming	SERPINF1	NOS26-0110	613982
Defects in collagen modification
VII	AR	Lethal (Null)/ Severe/	Severe perinatal	CRTAP	NOS26-0050	610682
		Severe (Hypomorphic)	Progressively deforming	CRTAP	NOS26-0120	610682
			Moderate	CRTAP	NOS26-0310	610682
VIII	AR	Lethal	Severe perinatal	P3H1 (LEPRE1)	NOS26-0060	610915
		Severe	Progressively deforming	P3H1 (LEPRE1)	NOS26-0130	610915
IX	AR	Lethal	Severe perinatal	PPIB	NOS26-0070	259440
			Progressively deforming	PPIB	NOS26-0140	259440
		Moderate	Moderate	PPIB	NOS26-0320	259440
XIV	AR	Severe	Progressively deforming	TMEM38B	NOS26-0170	615066
Defects in collagen folding and cross-linking
X	AR	Severe/Lethal	Progressively deforming	SERPINH1	NOS26-0150	613848
XI /	AR	Severe	Progressively deforming	FKBP10	NOS26-0160	610968
BRKS1		Mild	Moderate	FKBP10	NOS26-0330	610968
		Bruck syndrome type 1	Bruck syndrome type 1	FKBP10	NOS26-0430	259450
BRKS2	AR	Bruck syndrome type 2	Bruck syndrome type 2	PLOD2	NOS26-0440	609220
Defects in osteoblast development with collagen insufficiency
XII	AR	Severe	Moderate	SP7	NOS26-0340	613849
XV	AR	Severe	Progressively deforming	WNT1	NOS26-0190	615220
			Moderate	WNT1	NOS26-0290	166220
XVI	AR	Severe	Progressively deforming	CREB3L1	NOS26-0200	616229
XVII	AR	Progressive Severe	Progressively deforming	SPARC	NOS26-0210	616507
XVIII	XLR	Moderate/Severe	Progressively deforming	MBTPS2	NOS26-0230	301014
XIX	AR	Severe	Progressively deforming	FAM46A/TENT5A	NOS26-0220	617952
XX	AR	Progressive Severe/Lethal	Progressively deforming	MESD	NOS26-0240	618644
XXI	AR	Severe + Neurodevelopmental	Progressively deforming with neurodevel- opmental features	KDELR2	NOS26-0250	619131
XXII	AR	Severe	Progressively deforming	CCDC134	NOS26-0260	619795
Other bone fragility disorders
	AD		OI with craniosynostosis (Cole Carpenter syndrome)	P4HB	NOS26-0360	112240
	AR		OI with craniosynostosis (Cole Carpenter syndrome)	SEC24D	NOS26-0370	616294
	XL		Osteoporosis X-linked form	PLS3	NOS26-0380	300910
	XL		Osteoporosis X-linked form	MBTPS2	NOS26-0390	301014
	AD		Osteoporosis - dominant form	WNT1	NOS26-0400	615220
	AD		Osteoporosis - dominant form	LRP5	NOS26-0410	166710,601884
	AD		Osteoporosis - dominant form	ARHGAP25	NOS26-0420	610587
	AR		Osteoporosis-pseudoglioma syndrome	LRP5	NOS26-0450	259770
	AD		Bone fragility with calvarial "doughnut" lesions	SGMS2	NOS26-0460	126550

Clinical EDS subtype	Inheritance	Group	Protein	Gene	2023 Skeletal dysplasia nosology code [⁸8 Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–209. https://doi.org/10.1002/ajmg.a.63132. https://doi.org/10.1002/ajmg.a.63132... ]	OMIM Condition [¹²12 Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {Accessed December 10th, 2023}. https://omim.org/. https://omim.org/... ]
1 Classical EDS (cEDS)	AD	Defects in collagen primary structure and collagen processing	Type V collagen	COL5A1
			Type V collagen	COL5A2		130010
			Type I collagen	Rare: COL1A1 c.934C>T, p.(Arg312Cys)
2 Classical-like EDS (clEDS)	AR	Defects in structure and function of myomatrix, the interface between muscle and ECM	Tenascin XB	TNXB		606408
3 Cardiac-valvular EDS (cvEDS)	AR	Defects in collagen primary structure and collagen processing	Type I collagen	COL1A2 (biallelic variants that lead to COL1A2 NMD and absence of pro α2(I) collagen chains)		225320
4 Vascular EDS (vEDS)	AD	Defects in collagen primary structure and collagen processing	Type III collagen	COL3A1		130050
			Type I collagen	COL1A1 c.934C>T, p.(Arg312Cys) c.1720C>T, p.(Arg574Cys) c.3227C>T, p.(Arg1093Cys)
5 Hypermobile EDS (hEDS)	AD	Unknown	Unknown	Unknown		130020
6 Arthrochalasia EDS (aEDS)	AD	Defects in collagen primary structure and collagen processing	Type I collagen	COL1A1COL1A2		130060 130060
7 Dermatosparaxis EDS (dEDS)	AR	Defects in collagen primary structure and collagen processing	ADAMTS-2	ADAMTS2		225410
8 Kyphoscoliotic EDS (kEDS)	AR	Defects in collagen folding and collagen cross-linking	Lysylhydroxylase 1	PLOD1		225400
			FKBP22	FKBP14		614557
9 Brittle Cornea syndrome (BCS)	AR	Disorders of intracellular processes	ZNF469 PRDM5	ZNF469 PRDM5		229200 614170
10 Spondylodysplastic EDS (spEDS)	AR	Defects in glycosaminoglycan biosynthesis	β4GalT7 β3GalT6	B4GALT7 B3GALT6	NOS05-0070 NOS05-0060^* * Also termed Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type), B3GALT6-related.	130070, 615349 271640
		Disorders of intracellular processes	ZIP13	SLC39A13	NOS13-0230	612350
11 Musculocontractural EDS (mcEDS)	AR	Defects in glycosaminoglycan biosynthesis	D4ST1 DSE	CHST14 DSE	NOS04-0090 NOS04-0100	601776 615539
12 Myopathic EDS (mEDS)	AD or AR	Defects in structure and function of myomatrix, the interface between muscle and ECM	Type XII collagen	COL12A1		616471
13 Periodontal EDS^# # Also considered as Inborn Errors of Immunity (complement deficiencies) [20]	AD GOF	Defects in complement pathway	C1r	C1R		130080
(pEDS)			C1s	C1S		130080

Systemic Features Scoring (maximum: 20 points; score ≥ 7 indicates systemic involvement)
Wrist AND thumb signs^# # The "wrist sign" is positive when the thumb overlaps the fifth finger when grasping the contralateral wrist. The "thumb sign" is positive when it protrudes beyond the edge of the clenched fist							3
Wrist OR thumb sign^# # The "wrist sign" is positive when the thumb overlaps the fifth finger when grasping the contralateral wrist. The "thumb sign" is positive when it protrudes beyond the edge of the clenched fist							1
Pectus carinatum deformity							2
Pectus excavatum or chest asymmetry							1
Hindfoot deformity							2
Plain pes planus							1
Pneumothorax							2
Dural ectasia							2
Protrusio acetabuli							2
Reduced upper segment/lower segment ratio AND increased arm/height AND no severe scoliosis							1
Scoliosis or thoracolumbar kyphosis							1
Reduced elbow extension							1
Facial features (3/5)							1
dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia Skin striae							1
Myopia > 3 diopters							1
Mitral valve prolapse (all types)							1
Diagnostic criteria ^* * Individuals with features suggestive of other syndromes, such as Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, congenital contractural arachnodactyly, familial thoracic aortic aneurysms, and dissection, and vascular Ehlers-Danlos syndrome, need to have these diagnoses excluded through genetic testing Family History Negative Marfan Syndrome
	Aortic diameter at the sinuses of Valsalva ≥ Z-score 2, or aortic root dissection	+	Ectopia LentisFBN1 Systemic Features ≥ 7 points
	Ectopia Lentis	+	FBN1 variant with known association with aortic enlargement or dissection
Ectopia Lentis Syndrome	Ectopia Lentis	+ -	FBN1 variant without known association with aortic enlargement or dissection	+ -	Systemic Features
MASS	Aortic diameter at the sinuses of Valsalva < Z-score 2	+	Systemic Features ≥ 5 points (at least one skeletal feature)	–	Ectopia Lentis
MVPS	Mitral Valve Prolapse	+	Aortic diameter at the sinuses of Valsalva < Z-score 2	+	Systemic Features < 5 points	–	Ectopia Lentis
Family History PositiveMarfan Syndrome	Positive Family History	+	Ectopia Lentis Systemic Features ≥ 7 points Aortic diameter at the sinuses of Valsalva ≥ Z-score 2, above age 20 years Aortic diameter at the sinuses of Valsalva ≥ Z-score 3, below age 20 years

LDS type	Gene	OMIM [¹²12 Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {Accessed December 10th, 2023}. https://omim.org/. https://omim.org/... ]	Chromosome	2023 Skeletal dysplasia nosology [⁸8 Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–209. https://doi.org/10.1002/ajmg.a.63132. https://doi.org/10.1002/ajmg.a.63132... ]
LDS1	TGFBR1	609192	9q22	NOS 31-0030
LDS2	TGFBR2	610168	3p24	NOS 31-0040
LDS3	SMAD3	613795	15q	NOS 31-0080
LDS4	TGFB2	614816	1q41	NOS 31-0050
LDS5	TGFB3	615582	14q24	NOS 31-0060
LDS6	SMAD2	619656	18q21	NOS 31-0070

[1] *Correspondence: Nilton Salles Rosa Neto nsalles@yahoo.com

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Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders

Abstract