Hereditary Disorders

Traditional Sanger sequencing techniques are used to interrogate gene sequences in a step wise fashion; in complex disease where multiple genes are involved this can lead to costly and lengthy investigations. The advantage of next generation sequencing platforms is their ability to sequence many genes in parallel. Applied in the clinical setting this enables rapid diagnosis and timely decisions on appropriate treatment pathways.

Sample Type: 4.5ml EDTA blood or 4µg of DNA suspended in TE buffer at a concentration of = 50ng/µl

Sequencing: Illumina MiSeq, sequencing at a read depth of 50x for a minimum of 98% of the bases

Confirmation: Bi-directional Sanger sequencing confirmation of mutation positive samples

Reporting times: 6-8 weeks

Referral form download

Alport Syndrome

Alport syndrome (AS) is an inherited, progressive disorder of renal, ocular and cochlear basement membranes. Clinically, it presents as a progressive inherited nephropathy. Symptoms include haematuria, proteinuria, high blood pressure, possible deafness and possible vision problems.

Alport Syndrome is a genetically heterogeneous disease arising from mutations in the genes coding for basement membrane type IV collagen. Mutations in any of these genes prevent the correct production or assembly of the type IV collagen network. Using massively parallel sequencing technologies all multiple genes can be sequenced simultaneously providing a rapid and cost effective service.

Features of the NewGene Alport Syndrome multigene panel

• The ALPORT MASTR amplifies the coding regions of each of the genes COL4A3, COL4A4 and COL4A5.

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Aortopathy Panel

Aortopathies are a group of complex, related disorders with overlapping phenotypes and genetic heterogeneity. They can be characterized by aneurysms, dilation, and tortuosity of the aorta that occur as a result of disruption to the genes involved in connective tissues and those related to the structure and function of the aortic wall.

Aortopathy can be treated using targeted therapy and/or appropriate interventional surgery, therefore an accurate genetic diagnosis is important. The NewGene Aortopathy panel includes 15 genes implicated in the following disorders:

• Marfan syndrome
• Loeys-Dietz syndrome type 1A and type 2A
• Loeys-Dietz syndrome type 1B and type 2B
• Loeys-Dietz syndrome type 1C also known as aneurysm-osteoarthritis syndrome
• Ehlers-Danlos syndrome type IV, autosomal dominant
• Thoracic aortic aneurysms and aortic dissections/aortic aneurysm, familial thoracic TAAD/AAT
• Arthrogryposis, distal, type 9/contractural arachnodactyly, congenital
• Arterial tortuosity syndrome
• Aortic valve disease-1
• X-linked cardiac valvular dysplasia.

Genes included in the assay:

FBN1, TGFBR1, TGFBR2, ACTA2, SMAD3, MYH11, COL3A1, EFEMP2 (FBLN4), FBN2, MYLK, NOTCH1, SLC2A10, FLNA, TGFB2, SKI.

Features of the NewGene Aortopathy Panel

• Haloplex-based target enrichment
• Sequencing of coding regions and splice sites +/-10bp
• 100% coverage of critical genes (marked in bold above)

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Hereditary Breast Cancer - BRCA 1 and BRCA 2

Over 40,000 new cases of breast cancer are recorded each year in the UK. Most of these arise from sporadic mutations, however up to 10% are due to inherited mutations in breast cancer susceptibility genes. Full mutation screening for BRCA 1 and BRCA 2 is currently available for those patients who are considered to be at high risk (>20%).

Features of NewGene's Breast Cancer Test:

• Full gene sequencing across the coding regions and intron / exon boundaries of both BRCA 1 and 2
• Multiplex Ligation Dependent Probe Amplification (MLPA) to detect deletions and insertions

Referral form download

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RASopathy gene panel

Introducing direct delivery of the NewGene RASopathy gene panel, a comprehensive diagnostic test for all Noonan spectrum disorders.

• Noonan syndrome
• Noonan-like syndrome disorder with or without juvenile myelomonocytic leukaemia (NSLL)
• Noonan-like syndrome with loose anagen hair (NSLH)
• Cardio-facio-cutaneous syndrome (CFC)
• Costello syndrome
• LEOPARD syndrome (multiple lentigines syndrome)
• Legius syndrome (Neurofibromatosis type 1-like syndrome)

Based on next generation sequencing technology the RASopathy Test simultaneously screens all coding regions and splice sites of 15 genes for the mutations causative of all the RASopathy disorders. This comprehensive test replaces the current multi-stage strategy that is both time-consuming and costly and reduces the likelihood of missed molecular diagnosis.

Genes included in the assay:

PTPN11, BRAF, SOS1, RAF1, KRAS, HRAS, NRAS, SHOC2, CBL, SPRED1, MAP2K1, MAP2K2, RIT1, A2ML1 and NF1.

Features of the RASopathy gene panel

• Pre-screen for mutations in exons 3 and 8 of the PTPN11 gene found in 15-20% of Noonan syndrome patients
• RASopathy gene panel Full gene sequencing of all causative exons and intron / exon boundaries in 15 genes
• Familial tests for known mutations.

Referral form download

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Familial Hypercholesterolaemia

Familial Hypercholesterolaemia (FH) is a genetic disorder characterised by high LDL-cholesterol levels causing premature cardiovascular disease. Although one of the commonest inherited conditions, affecting around 1 in 500 people, it is asymptomatic and therefore under-diagnosed with 85% of those affected remaining unidentified (Marks et al, 2004).

The key to improving outcomes is early identification and initiation of treatment, effectively eliminating the excess cardiovascular risk (Betteridge et al, 1999; Neil et al, 2008; Vermissen et al, 2008).

NewGene offers a two step testing regime with a rapid low cost genotype assay for common mutations, followed by full gene sequencing if required. In the North East and North Cumbria region the clinical phenotype as measured on the Dutch Clinic Score is used to determine the testing process.

Features of the NewGene Familial Hypercholesterolaemia Service:

• Rapid genotyping test for common mutations in the LDLR, APOB and PCSK9 genes is offered to patients with suspected FH and a Dutch Clinic Score of 6 or more
• If the genotyping result is negative, and the patient’s clinical score is less then 10, the result is reported and the next steps determined at an MDT. If appropriate the patient can be referred for full gene sequencing.
• If the genotype result is negative and the clinical score is 10 or greater, the sample will automatically progress to full gene sequencing.
• The full gene sequencing assay includes coding and promoter regions of LDLR, PCSK9 and APOE, plus exon 26 of APOB

Samples

All samples for testing should be submitted to the Northern Genetics Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust.

Reporting

Referring clinicians will receive a fully interpreted report that has been approved by an HCPC registered Clinical Scientist from the Northern Genetics Service.

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Hereditary forms of Colorectal Cancer

Most people who develop bowel cancer have no family history of the disease, however for around 25% of all bowel cancer cases diagnosed in the UK there are affected family members. The 2 most common inherited colorectal cancer syndromes are hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP).

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colon cancer, accounting for about 3% of all colorectal cancer diagnoses each year. If a patient has a mutation in an associated gene their risk of being affected is very high. It also leads to increased risk of other cancers; kidney, ovarian, uterine, renal pelvis, small intestine, and stomach cancer.

Familial adenomatous polyposis (FAP) is a rare condition characterized by the presence of hundreds or even thousands of benign polyps, or growths in the large intestine. It is thought to be present in about 1% of all people diagnosed with colorectal cancer each year.

Features of NewGene's HNPCC Test:

• Full gene sequencing of the coding region of four genes: MLH1, MSH2, MSH6 (excluding exon 1) and PMS2
• Sequencing of the 3’ untranslated region of EPCAM

Features of NewGene's FAP Test:

• Full gene sequencing of the APC and MUTYH genes

For both tests Multiplex Ligation Dependent Probe Amplification (MLPA) will be carried out to detect deletions and insertions.

Referral form download

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