Genetics · MU Sofia

45. Contiguous gene syndromes: DiGeorge syndrome; Williams syndrome.

Covers contiguous gene syndromes as a group, explaining how loss of neighbouring genes produces combined haploinsufficiency, then walks through DiGeorge (22q11.2 deletion) and Williams syndrome in turn. For each it gives the genetic basis, pathogenesis, clinical features, diagnostic tests and management. It includes the CATCH-22 mnemonic for DiGeorge syndrome and a description of the Williams syndrome facial features and behavioural profile.

Inside: 4 sections · 5 labelled pictures · 14 flashcards · 3 min

Topic 45 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 4 sections, about 432 words (3 min of reading), with 14 flashcards.

In this note

  1. Contiguous gene syndromes: DiGeorge syndrome; Williams syndrome.
  2. General Pathogenesis of Contiguous Gene Syndromes
  3. I. DiGeorge Syndrome (22q11.2 Deletion Syndrome)
  4. II. Williams Syndrome

Contiguous gene syndromes: DiGeorge syndrome; Williams syndrome.

Contiguous gene syndromes are genetic disorders caused by deletion (or duplication) of a chromosomal segment containing multiple neighboring genes. The phenotype results from the combined haploinsufficiency of several adjacent genes, not a single gene defect.

Key characteristics:

  • Usually caused by microdeletions
  • Not visible on routine karyotyping
  • Detected by FISH, MLPA, or chromosomal microarray (aCGH)
  • Often show multisystem involvement

General Pathogenesis of Contiguous Gene Syndromes

  1. 1. Loss of a chromosomal region containing multiple functionally unrelated genes.
  2. 2. Reduced dosage (haploinsufficiency) of several genes simultaneously.
  3. 3. Disruption of multiple developmental pathways.
  4. 4. Results in complex, characteristic syndromic phenotypes.

I. DiGeorge Syndrome (22q11.2 Deletion Syndrome)

DiGeorge syndrome is a contiguous gene syndrome caused by a microdeletion on chromosome 22q11.2, characterized by cardiac defects, immunodeficiency, hypocalcemia, and craniofacial abnormalities.

Genetic Basis

  • Chromosome: 22q11.2
  • Type of defect: Microdeletion
  • Key gene involved: TBX1 (critical for pharyngeal arch development)

Most cases are sporadic, but autosomal dominant inheritance can occur.

Pathogenesis

  1. 1. Deletion of genes controlling pharyngeal arch and pouch development.
  2. 2. Abnormal development of the third and fourth pharyngeal pouches.
  3. 3. Hypoplasia or aplasia of:
  • thymus,
  • parathyroid glands.
  1. 4. Resulting immune, endocrine, and cardiac abnormalities.

Clinical Features

Cardiovascular

  • Conotruncal heart defects: Tetralogy of Fallot
  • Truncus arteriosus
  • Interrupted aortic arch

Immune System

  • Thymic hypoplasia or aplasia
  • T-cell immunodeficiency
  • Recurrent viral and fungal infections

Endocrine / Metabolic

  • Hypocalcemia due to hypoparathyroidism
  • Seizures secondary to low calcium

Craniofacial

  • Cleft palate
  • Micrognathia
  • Low-set ears
  • Long face

Neuropsychiatric

  • Developmental delay
  • Learning difficulties
  • Increased risk of psychiatric disorders in adolescence/adulthood

Mnemonic: CATCH-22

  • Cardiac defects
  • Abnormal facies
  • Thymic hypoplasi
  • Cleft palate
  • Hypocalcemia

Diagnosis

  • FISH using 22q11.2 probe
  • Chromosomal microarray (aCGH)
  • Immunological testing (T-cell counts)
  • Serum calcium levels

Management

  • Correction of cardiac defects
  • Calcium and vitamin D supplementation
  • Infection prevention and immunologic follow-up
  • Speech and developmental therapy

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