165: The 22q11.2 Deletion Syndrome

Key Points

  • Disease summary:

    • The 22q11.2 deletion (22q11.2DS) has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome, and in some individuals with autosomal dominant Opitz G/BBB syndrome and Cayler cardiofacial syndrome (asymmetric crying facies).

    • The most frequent significant clinical features in individuals with 22q11.2 deletion include the following: immunodeficiency, congenital heart disease, palatal defects, hypocalcemia, renal anomalies and dysphagia, and developmental disabilities.

    • 85% of individuals have the same large greater than 3 Mb hemizygous deletion (referred to as A-D) involving approximately 45 functional genes including TBX1, a member of the T-box transcription factor family of genes, known to play a crucial role in development.

    • Conversely, 15% of individuals have “nested” or atypical deletions which may or may not include TBX1 as it resides between low copy repeat (LCR) blocks A-B.

    • Nested deletions may include A-B, A-C, B-C, B-D, C-D.

    • Phenotypic features in Individuals with deletions which do not include A-B/TBX1 are similar to those with the full standard deletion suggesting either a downstream effect of TBX1 and/or the importance of other downstream genes such as CRKL1 located between C and D.

    • Variable expressivity may be due to stochastic, environmental, and/or genetic factors such as modifier genes or variations in the remaining allele of TBX1. See Table 165-1 for a summary of molecular genetic testing associated with 22q11.2 DS.

    Hereditary basis:

    • 22q11.2DS most often occurs as a de novo event.

    • Approximately 10% of cases are familial and affected individuals have a 50% recurrence risk.

    • Germline and somatic mosaicism has been observed so parental testing and prenatal monitoring is suggested.

    • Inter- and intrafamilial phenotypic variability is common including between identical twins.

  • Differential diagnosis:

    • Structural anomalies found in association with 22q11.2DS can also be observed as an isolated finding in an otherwise normal individual.

    • Syndromes with overlapping features include Smith-Lemli-Opitz, Alagille, VATER, oculo-auriculo-vertebral spectrum or Goldenhar, and Kabuki.

    • Individuals with both unicoronal and bicoronal craniosynostosis in whom molecular causes for known craniosynostosis syndromes have been excluded are candidates for deletion studies.

    • Individuals suspected of having 22q11.2DS with negative fluorescence in situ hybridization (FISH) studies may have a smaller nested or atypical deletion within 22q11.2 which will require further study using multiplex ligation-dependent probe amplification (MLPA) or array technology; aneuploidy involving some other chromosomal region such as a cytogenetically detectable 10p13-10p14 deletion; a mutation in TBX1; or a mutation in CHD7, associated with CHARGE syndrome.

    • It is important to note that individuals with 22q11.2DS have presented with concomitant diagnoses such as those detailed in Table 165-2.

Table 165-1   Molecular Genetic Testing 

Table 165-2   System Involvement