Distal arthrogryposes (DA) and lethal congenital contracture syndrome (LCCS) are clinically related, genetically heterogeneous groups of disorders. DA is characterized by non-progressive congenital contractures of the upper and lower limbs not due to a primary neurologic or muscle disease. Other common findings include camptodactyly, clubfoot, facial dysmorphism, epicanthal folds, strabismus, ptosis, short stature and scoliosis. LCCS is more severe. Typical findings include multiple congenital joint contractures, intrauterine growth retardation, dysmorphic facial features, pulmonary hypoplasia, muscular atrophy, decreased fetal movement and polyhydramnios. Akinesia, hypotonia, areflexia, diaphragmatic atrophy and pterygium may also be present.
The congenital contracture syndrome extended NGS Panel consists of thirty-one genes: ADCY6, ADGRG6, CHRNA1, CHRND, CHRNG, CNTNAP1, DNM2, DOK7, ECEL1, ERBB3, FBN2, GLDN, GLE1, LGI4, LMNA, MUSK, MYBPC1, MYH3, MYH8, NALCN, NEK9, PIEZO2, PIP5K1C, RAPSN, TNNI2, TNNT3, TPM2, VIPAS39, VPS33B, ZBTB42 and ZMPSTE24.
Copy number variation (CNV) analysis of the congenital contracture syndrome extended panel genes is also offered. Additionally, CTGT offers a comprehensive test (both NGS and CNV panels) for these genes. Panel genes are also offered as individual sequencing and deletion/duplication tests, unless otherwise indicated.
Gene |
Disorder |
MIM |
Inheritance |
ADCY6 |
Lethal congenital contracture syndrome 8 (LCCS8) |
616287 |
AR |
ADGRG6 |
Lethal congenital contracture syndrome 9 (LCCS9) |
616503 |
AR |
CHRNA1 |
Multiple pterygium syndrome, lethal type (LMPS) Myasthenic syndrome, congenital, 1A, slow-channel (CMS1A) Myasthenic syndrome, congenital, 1B, fast-channel (CMS1B) |
253290 601462 608930 |
AR AD AR / AD |
CHRND |
Multiple pterygium syndrome, lethal type (LMPS) Myasthenic syndrome, congenital, 3A, slow-channel (CMS3A) Myasthenic syndrome, congenital, 3B, fast-channel (CMS3B) Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency (CMS3C) |
253290 616321 616322 616323 |
AR AD AR AR |
CHRNG |
Multiple pterygium syndrome, lethal type (LMPS) Multiple pterygium syndrome, Escobar variant (EVMPS) |
253290 265000 |
AR AR |
CNTNAP1 |
Lethal congenital contracture syndrome 7 (LCCS7) |
616286 |
AR |
DNM2 |
Lethal congenital contracture syndrome 5 (LCCS5) Charcot-Marie-Tooth disease, dominant intermediate B (CMTDIB) Myopathy, centronuclear 1 (CNM1) |
615368 606482 160150 |
AR AD AD |
DOK7 |
Fetal akinesia deformation sequence (FADS) Myasthenic syndrome, congenital, 10 (CMS10) |
208150 254300 |
AR AR |
ECEL1 |
Arthrogryposis, distal, type 5D (DA5D) |
615065 |
AR |
ERBB3 |
Lethal congenital contracture syndrome 2 (LCCS2) |
607598 |
AR |
FBN2 |
Arthrogryposis, distal, type 9 (DA9) (Contractural arachnodactyly, congenital; CCA) |
121050 |
AD |
GLDN |
Lethal congenital contracture syndrome 11 (LCCS11) |
617194 |
AR |
GLE1 |
Lethal congenital contracture syndrome 1 (LCCS1) Arthrogryposis, lethal, with anterior horn cell disease (LAAHD) |
253310 611890 |
AR AR |
LGI4 |
Arthrogryposis multiplex congenita, LGI4 related |
- |
AR |
LMNA |
Restrictive dermopathy, lethal Charcot-Marie-Tooth disease, axonal, type 2B1 (CMT2B1) Emery-Dreifuss muscular dystrophy 2, autosomal dominant (EDMD2) Emery-Dreifuss muscular dystrophy 3, autosomal recessive (EDMD3) Mandibuloacral dysplasia (MADA) Muscular dystrophy, congenital, LMNA related Muscular dystrophy, limb-girdle, type 1B (LGMD1B) |
275210 605588 181350 616516 248370 613205 159001 |
AR AR AD AR AR AD AD |
MUSK |
Fetal akinesia deformation sequence (FADS) Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency (CMS9) |
208150 616325 |
AR AR |
MYBPC1 |
Lethal congenital contracture syndrome 4 (LCCS4) Arthrogryposis, distal, type 1B (DA1B) |
614915 614335 |
AR AD |
MYH3 |
Arthrogryposis, distal, type 2A (DA2A) Arthrogryposis, distal, type 2B (DA2B) Arthrogryposis, distal, type 8 (DA8) |
193700 601680 178110 |
AD AD AD |
MYH8 |
Arthrogryposis, distal, type 7 (DA7) |
158300 |
AD |
NALCN |
Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (IHPRF1) |
616266
615419
|
AD
AR
|
NEK9 |
Lethal congenital contracture syndrome 10 (LCCS10) Arthrogryposis, Perthes disease, and upward gaze palsy (APUG) |
617022 614262 |
AR AR |
PIEZO2 |
Arthrogryposis, distal, type 3 (DA3) Arthrogryposis, distal, type 5 (DA5) Arthrogryposis, distal, with impaired proprioception and touch (DAIPT) Marden-Walker syndrome (MWKS) |
114300 108145 617146 248700 |
AD AD AR AD |
PIP5K1C |
Lethal congenital contracture syndrome 3 (LCCS3) |
611369 |
AR |
RAPSN |
Fetal akinesia deformation sequence (FADS) Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (CMS11) |
208150 616326 |
AR AR |
TNNI2 |
Arthrogryposis, distal, type 2B (DA2B) |
601680 |
AD |
TNNT3 |
Arthrogryposis, distal, type 2B (DA2B) |
601680 |
AD |
TPM2 |
Arthrogryposis, distal, type 1A (DA1A) Arthrogryposis, distal, type 2B (DA2B) Nemaline myopathy 4, autosomal dominant (NEM4) |
108120 601680 609285 |
AD AD AD |
VIPAS39 |
Arthrogryposis, renal dysfunction, and cholestasis 2 (ARCS2) |
613404 |
AR |
VPS33B |
Arthrogryposis, renal dysfunction, and cholestasis 1 (ARCS1) |
208085 |
AR |
ZBTB42 |
Lethal congenital contracture syndrome 6 (LCCS6) |
616248 |
AR |
ZMPSTE24 |
Restrictive dermopathy, lethal Mandibuloacral dysplasia with type B lipodystrophy (MADB) |
275210 608612 |
AR AR |
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