Clinical Genetics (Diagnostics L1)

Prevalence of Disease

• 50% of 1st trimester pregnancy losses have a chromosomal cause
• Genetic disorders account for:
  • 50% of childhood blindness
  • 50% of childhood deafness
  • 50% of severe learning difficulty
• 30% of childhood hospital admissions due to genetic disorders and congenital malformations
• 50% of childhood deaths due to genetic disorders and congential malformations

Type of Referral to Clinical Service

• Diagnostic opinion: dysmorphic child or abnormal antenatal scan
• New diagnosis of genetic disorder in adult/child
• Known suspected family history of genetic disorder
• Positive carrier test result from population screening programme e.g. Cystic fibrosis
• Strong family history of cancer
• Possible inherited cardiac disease
• Genetic variant found via genetic testing

Autosomal Dominant Inheritance

• Males and females affected
• Male-male transmission
• 50% risk to offspring of affected person
• New mutations common e.g. achondroplasia, neurofibromatosis
• De novo mutations can occur in egg/sperm giving the child a dominant disorder but the parents wouldn't carry the mutation
• Some triple repeat disorders like Huntington's, Myotonic dystrophy
• Inherited cardiac disorders like Marfan syndrome, Long QT syndrome, hypertrophic cardiomyopathy
• Neurocutaneous syndromes - NF1, Tuberous Sclerosis
• Many others - ADPKD, cancer predisposition (BRCA, Lynch, MEN1), von Hippel Lindau, paediatric dysmorphology syndromes like Noonan, Stickler, Cornelia de Lange

Marfan

• Inherited connective tissue dominant disorder
• 1 in 3000 - 1 in 5000
• Vast majority will have an identifiable FBN1 gene mutation. FBN1 codes for Fibrillin 1
• Skeletal, ocular, cardiac phenotype
• Symptoms: eye lens problems, long fingers/arm span, raised part of chest wall, ankle problem, stretch marks, flat feet, long face, eyes down slant, flattened cheek bone
• Cardiac disorder than results in aortic dilation - regular heart check ups required
• Aortic root is the measurement at the sinuses of Valsalva
• Z score ≥ 2 (when standardised to age and body size)
• Marfan phenotype due to increased TGFbeta, Angiotensin receptor blockers decrease TGFbeta
• Can have elective surgery due to aortic dilation

Case:

• 18 paediatric patients with Marfan syndrome
• Previous medical therapies had…