Birt-Hogg-Dube syndrome (Primary spontaneous pneumothorax)

The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include fibrofolliculomas (specific cutaneous lesions), pulmonary cysts/history of pneumothorax, and various types of renal tumors [64]. Disease severity can vary significantly among family members and between families [64]FLCN is the only gene in which pathogenic variants are known to cause BHDS and it is thought to be inherited in an autosomal dominant manner with 100% penetrance [64].

Gene name Transcript Clinical sensitivity
FLCN ENST00000285071.4 69-88% [65-67]
SERPINA1 ENST00000448921  
TSC1 ENST00000298552  
TSC2 ENST00000219476  

Capillary malformation-arteriovenous malformation/Parker-Weber syndrome

RASA1-related disorders are characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs [68]. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences [68]. Symptoms from intracranial AVMs/AVFs appear to occur early in life [68]. Several individuals have RASA1-related Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft-tissue and skeletal growth of an affected limb) [68]RASA1-related disorders are inherited in an autosomal dominant manner. About 70% of affected individuals have an affected parent; about 30% have a de-novo pathogenic variant [68].

Gene name Transcript Clinical sensitivity
RASA1 ENST00000274376.6 35-85% [69-71]

Hereditary Haemorrhagic Telaniectasia (HHT)

Hereditary hemorrhagic telangiectasia (HHT) is characterised by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins [72]. HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability and most individuals have an affected parent [72]. Currently, all known genetic defects that cause HHT are in genes that encode proteins within the transforming growth factor beta (TGF-β) signaling pathway [72].

Gene name Transcript Clinical sensitivity
ENG ENST00000373203.4 39-59% [72]
ACVRL1 ENST00000388922.4  25-57% [72
SMAD4  ENST00000342988.3  1-2% [72
KRIT1  ENST00000394507.1  n/a 


The most common form of homocystinuria is characterised by near-sightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to osteoporosis or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems [73]Mutations in the CBS cause the most common form of homocystinuria. CBS encodes cystathionine beta-synthase, responsible for converting the homocysteine amino acid to cystathionine. As a result of this pathway, other amino acids, including methionine, are produced. Mutations in the CBS gene disrupt the function of cystathionine beta-synthase, preventing complete metabolism of homocysteine. As a result, this amino acid and toxic byproducts build up in the blood, some of which are excreted via urine [73]

Gene name Transcript Clinical sensitivity
CBS ENST00000263967.3 91-94% [74, 75]
MTHFR ENST00000376590.3  ~27% [76]

Megalencephaly Capillary Malformation Syndrome 

MCAP syndrome is characterised by the major findings of megalencephaly associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability; and cutaneous capillary malformations with focal or generalised somatic overgrowth. Additional findings can include digital anomalies (syndactyly, polydactyly), cortical malformations – most distinctively polymicrogyria and variable connective tissue dysplasia [77]. 

PIK3CA-associated segmental overgrowth is not typically inherited. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in PIK3CA, suggesting that the mutation occurred post-fertilisation in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline pathogenic variant in PIK3CA. All reported individuals with CLOVES syndrome (congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies) and FH (fibroadipose hyperplasia) had somatic mosaicism for pathogenic variants in PIK3CA [77]. 

Gene name Transcript Clinical sensitivity
PIK3CA ENST00000263967.3 ~48% [78]

Microcephaly Capillary Malformation Syndrome (MCAP)

Microcephaly-capillary malformation syndrome is characterised by microcephaly, generalised cutaneous capillary malformations, hypoplastic distal phalanges of the hands and/or feet, intractable epilepsy, and profound developmental delay [79]. Microcephaly-capillary malformation (MIC-CAP) syndrome results from the presence of biallelic STAMBP pathogenic variants, most often one inherited from each parent [79]. 

Gene name Transcript Clinical sensitivity
STAMBP ENST00000394070.2

Polycystic kidney disease

Gene name Transcript Clinical sensitivity
PKD2 ENST00000237596.2  

Venous Malformations

Gene name Transcript Clinical sensitivity
GLMN ENST00000370360.3  
TEK  ENST00000380036.4  Not quantifiable due to rarity of the disease - studies suggest a high proportion of hereditary cutaneomucosal venous malformations are caused by pathogenic variants in this gene [80]


Clinical genetics and genomics laboratory

Ground floor (level 2), Sydney wing, Royal Brompton Hospital, Sydney Street, London, SW3 6NP

Telephone: 020 7352 8121 ext. 83009
Email: or 
Opening hours: Monday to Friday, 9 am to 5 pm
Head of laboratory: Dr Deborah Morris-Rosendahl

Useful documents

Molecular genetic testing request and consent form (pdf, 431KB)

Non-NHS molecular genetic testing request and consent form (pdf, 493KB)