Developmental disorders with cutaneous mosaicism are a group of skin diseases of the skin which affect its various components (vascular system, pigmentation, keratinocytes or adipocytes). These diseases are sometimes associated with segmental hypertrophy or central nervous system disorders. Within the past six years several genes have been identified by several international groups, including our team. These genes encode proteins belonging to the main PIK3CA-MTOR-AKT and RAS-MAPK signalling pathways, receptor tyrosine kinases and their ligand and heterotrimeric G proteins.
Back in 2010, high-throughput deep sequencing (deep HTS) became an innovative technology consisting in analysing targeted genes at a very deep level (>1000) in order to detect very slight degrees of variation (around 1%). Currently in use primarily for cancer diagnosis, it has been implemented by our laboratory mainly in the diagnosis of patients with mosaic skin disorders (cf. Figure). This technology is acknowledged in scientific publications as having the most relevance to these developmental diseases that have low allele balances, and for which numerous genes have been identified in recent years.
FHU TRANSLAD has pioneered the introduction of HTS for molecular diagnosis of rare diseases. Deep HTS is routinely applied in the molecular diagnosis of somatic mosaic-activating skin disorders within the FIMARAD network. Dijon Bourgogne University Hospital is the MAGEC (genetic diseases with cutaneous expression) reference centre, under the somatic mosaic-activating pathologies (UF9030 – Prof. Pierre VABRES, site director, Dr. Virginie CARMIGNAC scientific co-ordinator).
In 2017, Deep HTS was performed on 169 patients with somatic mosaic-activating skin disorders. The outcome was a positive molecular diagnosis in 64 (38%) of the patients. A total of 19 genes are examined through Deep-HTS on patients with somatic mosaic-activating skin disorderstique.
|
Analysis identifier |
Pathology diagnosed |
Gene |
Mutation |
Nbr of test that |
|
Targeted HTS sequencing of HRAS and KRAS genes |
Keratinocytic epidermal nevus Nevus sebaceus Schimmelpenning syndrome Phacomatosis pigmentokeratotica Oculoectodermal syndrome |
HRAS (NM_001130442.1) |
p.Gly12Asp p.GLy13Arg p.Gly13Val |
20 |
|
KRAS (NM_004985.3) |
p.Gly12Ser p.Gly12Asp p.Gly12Val p.Gln61His p.Ala146Thr |
|||
|
Targeted HTS sequencing of the FGFR3 gene |
Keratinocytic epidermal nevus |
FGFR3 (NM_000142.3) |
p.Arg248Cys p.Ser249Cys |
5 |
|
Targeted HTS sequencing of the FGFR2 gene |
Papillomatous nevus sebaceus Nevus acneiformis unilateralis |
FGFR2 (NM_000141.4) |
p.Cys382Arg p.Pro253Arg p.Tyr376Cys p.Ser252Trp |
10 |
|
Targeted HTS sequencing of the FGFR1 gene |
Encephalocraniocutaneous lipomatosis |
FGFR1 (NM_001174067.1) |
p.Asn546Glu p.Lys656Glu |
5 |
|
Targeted HTS sequencing of the NRAS gene |
Compound congenital melanocytic nevus Neurocutaneous melanosis |
NRAS (NM_002524.4) |
p.Gly13Arg p.Gln61Lys p.Gln61Arg p.Gln61His |
5 |
|
Targeted HTS sequencing of the BRAF gene |
Syringocystadenomatosus papilliferus Phacomatosis pigmentokeratotica |
BRAF (NM_004333.4) |
p.Lys601Asn p.Val600Glu p.Gly596Arg |
5 |
|
Targeted HTS sequencing of the KRT1 and KRT10 genes |
Epidermolytic epidermal nevus |
KRT1 (NM_006121.1) |
Complete sequence |
5 |
|
KRT10 (NM_000421.3) |
Complete sequence |
|||
|
Targeted HTS sequencing of GNAQ and GNA11 genes |
Port wine stain Sturge-Weber Syndrome Phakomatosis pigmentovascularis Extensive dermal melanocytosis |
GNAQ (NM_002072.3) |
p.Arg183Gln p.Gln209Pro |
60 |
|
GNA11 (NM_002067.2) |
p.Arg183Cys p.Arg183His |
|||
|
Targeted HTS sequencing of the MCAP PIK3CA- gene |
MCAP Syndrome |
PIK3CA (NM_006218.2) |
p.Glu726Lys p.Gly914Arg |
10 |
|
Targeted HTS sequencing of the CLOVES PIK3CA- gene |
CLOVES / Klippel-Trenaunay Syndrome |
PIK3CA (NM_006218.2) |
p.Glu542Lys p.Glu545Lys p.His1047Arg |
10-20 |
|
Targeted HTS sequencing of the PIK3CA gene |
Overgrowth syndrome / PROS |
PIK3CA (NM_006218.2) |
Complete sequence |
100 |
|
Targeted HTS sequencing of the AKT1 gene |
Proteus Syndrome |
AKT1 (NM_005163.2) |
p.Glu17Lys |
10 |
|
Targeted HTS sequencing of the TEK gene |
Venous malformations Bean's Syndrome |
TEK (NM_000459.3) |
Complete sequence |
10 |
|
Targeted HTS sequencing of the RASA1 gene |
Capillary-arteriovenous malformations |
RASA1 (NM_002890.1) |
Complete sequence |
5 |
|
Targeted HTS sequencing of the AKT3 gene |
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome |
AKT3 (NM_005465.4) |
Complete sequence |
5 |
|
Targeted HTS sequencing of the PIK3R2 gene |
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome |
PIK3R2 (NM_005027.2) |
Complete sequence |
5 |
|
Targeted HTS sequencing of the GLMN gene |
Venous malformations |
GLMN (NM_053274.2) |
Complete sequence |
5 |
|
Targeted HTS sequencing of the MTOR gene |
Hypomelanosis of Ito |
MTOR (NM_004958.3) |
Complete sequence |
15 |
List of genes linked to developmental disorders with mosaic-activating cutaneous manifestations studied at Dijon University Hospital