The CDL offers a testing panel sequencing 6 genes associated with Stickler syndrome.  Pathogenic variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2 genes, which code for type II, IX, and XII collagen, cause Stickler syndrome.

Stickler syndrome is a connective tissue disorder that may include ocular findings of myopia, cataract, and retinal detachment; hearing loss; midfacial underdevelopment and cleft palate; and mild spondylospiphyseal dysplasia and/or precocious arthritis.  The phenotype may be quite variable both within and between families.

The Core Ehlers-Danlos gDNA sequencing Panel includes testing for the classic and the vascular forms of Ehlers-Danlos syndrome.   The classic type of Ehlers-Danlos syndrome (EDS types I & II) is an autosomal dominant disorder characterized by skin hyperextensibility, increased skin fragility, joint hypermobility, and abnormal wound healing. Recent studies indicate that as many as 90% of individuals with EDS classic type have underlying pathogenic variants in COL5A1 or COL5A2, the genes that encode type V collagen.  The vascular form of Ehlers-Danlos syndrome (vEDS) is characterized by thin, translucent skin with visible veins; marked bruising; joint dislocations; and the major complications of arterial, bowel and uterine rupture.

Please consult the Ehlers-Danlos Syndrome Test Guide for more information on the diagnosis.

The CDL offers a core testing panel sequencing 3 genes involved in Alport syndrome.  Pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes, which code for type IV collagen, cause Alport syndrome. This panel is recommended for those individuals with possible autosomal recessive, autosomal dominant or X-linked Alport syndrome.  Genetic testing of COL4A5 as an individual gene is also offered for those families with clear X-linked inheritance pattern in their family.

Alport syndrome (AS) is a progressive glomerulonephritis characterized by kidney disease, hearing loss, and eye abnormalities. It has a prevalence of about 1 in 50,000 live births and may be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. The majority of affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys, and also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as the disease progresses, resulting in end-stage renal disease. Progressive sensorineural hearing loss during childhood or adolescence and ocular symptoms (including maculopathy, posterior polymorphous dystrophy, and recurrent corneal erosion) are common. Anterior lenticonus is considered to be virtually pathognomonic for Alport syndrome.

The classic type of Ehlers-Danlos syndrome (EDS types I & II) is an autosomal dominant disorder characterized by skin hyperextensibility, increased skin fragility, joint hypermobility, and abnormal wound healing. Recent studies indicate that as many as 90% of individuals with EDS classic type have underlying pathogenic variants in COL5A1 or COL5A2, the genes that encode type V collagen.

COL4A1 and COL4A2 encode the proα1(IV) and proα2(IV) chains, respectively, that form heterotrimers (2 proα1(IV) chains and a single proα2(IV) chain) in the type IV collagen that forms the vascular basement membranes outside the kidney and between tissues of different origins (e.g., epidermis and dermis in skin). Pathogenic variants in COL4A1 and COL4A2, have been associated with intracerebral hemorrhage in neonates and children, intracerebral hemorrhage and cerebral small vessel disease in adulthood, intracranial aneurysms, retinal arteriolar tortuosity, aneurysms and muscle cramp (HANAC) syndrome, infantile hemiparesis, and porencephaly.

The vascular form of Ehlers-Danlos syndrome (vEDS) is characterized by thin, translucent skin with visible veins; marked bruising; joint dislocations; and the major complications of arterial, bowel and uterine rupture.

The vast majority of probands in families with this form of EDS are identified on the basis of a major complication either bowel perforation or vascular aneurysm or rupture. The International Ehlers-Danlos Foundation Advisory Board set the following guidelines for determination of the clinical diagnosis of EDS type IV. DNA-based testing is recommended for those who meet these guidelines. Note, however, that individuals with nonsense mutations of COL3A1 are less likely to have similar physical characteristics. The clinical diagnosis of EDS type IV is highly suspected when two major diagnostic criteria are present:

Major clinical diagnostic criteria:

• Intestinal rupture
• Arterial rupture
• Uterine rupture during pregnancy
• Family history of the vascular type of EDS

Minor diagnostic criteria alone are not sufficient to warrant the diagnosis unless identified in an individual with a major criteria.

• Thin, translucent skin (especially noticeable on the chest/abdomen)
• Easy bruising (spontaneous or with minimal trauma)
• Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes)
• Acrogeria (an aged appearance to the extremities, particularly the hands)
• Hypermobility of small joints
• Tendon/muscle rupture
• Early-onset varicose veins
• Arteriovenous carotid-cavernous sinus fistula
• Pneumothorax/pneumohemothorax
• Chronic joint subluxations/dislocations
• Congenital dislocation of the hips
• Talipes equinovarus (clubfoot)
• Gingival recession

Please consult the Ehlers-Danlos Syndrome Test Guide for more information on the diagnosis.

Over 95% of the forms of OI (lethal and non-lethal) result from a single dominant mutation in either COL1A1 or COL1A2, the two genes that encode the chains of type I procollagen.  The phenotype that results from the disease-causing variant is a consequence of the underlying mutation type and location in the alpha 1 or alpha 2 chain of type I procollagen.  Null mutations of COL1A1 result in OI type I and missense mutations in either COL1A1 or COL1A2 result in variable phenotypes within a spectrum of age of onset, stature and deformity.

For guidelines on the correct test to order and for pertinent references, consult the Osteogenesis Imperfecta Test Guide.

Genetic testing of COL4A5 as an individual gene is offered for those families with clear X-linked inheritance of Alport Syndrome.

Alport syndrome (AS) is a progressive glomerulonephritis characterized by kidney disease, hearing loss, and eye abnormalities. It has a prevalence of about 1 in 50,000 live births and may be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. The majority of affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys, and also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as the disease progresses, resulting in end-stage renal disease. Progressive sensorineural hearing loss during childhood or adolescence and ocular symptoms (including maculopathy, posterior polymorphous dystrophy, and recurrent corneal erosion) are common. Anterior lenticonus is considered to be virtually pathognomonic for Alport syndrome.

Infantile cortical hyperostosis or Caffey disease is a dominantly inherited bone phenotype that is often identified in infancy with irritability, fever, soft tissue swelling and decreased movement of the involved limb.  Radiographs reveal subperiosteal new bone formation without fracture.  The hyperostosis of long bones, ribs or the mandible often resolves within months and may recur in childhood.  The clinical description in more recent reported families includes short stature, compression fractures, scoliosis and genu varus.  The disorder is associated with a c.3040C>T, p.Arg836Cys sequence variant, in exon 41 of COL1A1    The sensitivity of directed DNA sequencing of this region of COL1A1 in infants with the Caffey phenotype is roughly 90%.   The mechanism by which the variant contributes to the phenotype is presently unknown.

In infants (or pregnancies) with normal directed COL1A1 sequencing, a second recurrent Caffey phenotype has emerged.  In this population, the hyperostosis is prenatal in onset with many detected at premature delivery with poor lung maturation and stillbirth.  Recurrence in siblings born to unaffected parents is observed in this group.  Search for a genetic cause of this variable Caffey phenotype is ongoing.

EDS type VII, the Arthrochalasia type, is characterized by congenital hip dislocation, joint hypermobility, soft skin with normal scarring, easy bruising, blue sclerae, small jaw, and hypertrichosis.  It is typically identified in infancy.