Much progress is being made in the molecular diagnosis of Down syndrome prenatally. Approximately 5% to 10% of the total cell free DNA in maternal blood is derived from the fetus and can be identified by polymorphic genetic markers. By using next-generation sequencing, the gene dosage of chromosome 21-linked genes in fetal DNA can be determined with great precision. This has emerged as a sensitive and specific noninvasive method (“liquid biopsy”) for prenatal diagnosis of trisomy 21 as well as other trisomies. Currently, all cases of trisomy 21 identified by such liquid biopsies are confirmed by conventional cytogenetics on fetal cells obtained by amniocentesis.
22q11.2 Deletion Syndrome
The 22q11.2 deletion syndrome encompasses a spectrum of disorders that result from a small interstitial deletion of band 11 on the long arm of chromosome 22. The clinical features of this syndrome include congenital heart disease affecting the outflow tracts, abnormalities of the palate, facial dysmorphism, developmental delay, thymic hypoplasia with impaired T cell immunity (Chapter 5), and parathyroid hypoplasia resulting in hypocalcemia (Chapter 20). Previously, these clinical features were believed to represent two different disorders: DiGeorge syndrome and velocardiofacial syndrome. However, it is now known that both are caused by 22q11.2 deletion. Variations in the size and position of the deletion are thought to be responsible for the differing clinical manifestations. When T cell immunodeficiency and hypocalcemia are the dominant features, the patients are said to have DiGeorge syndrome, whereas patients with the so-called velocardiofacial syndrome have mild immunodeficiency and pronounced dysmorphology and cardiac defects. In addition to these malformations, patients with 22q11.2 deletion are at high risk for schizophrenia and bipolar disorder. In fact, it is estimated that schizophrenia develops in approximately 25% of adults with this syndrome. Conversely, deletions of the region can be found in 2% to 3% of individuals with childhood-onset schizophrenia. The molecular basis for this syndrome is not fully understood. The affected region of chromosome 11 encodes many genes. Among these, a transcription factor gene called TBX1 is suspected to be one of the responsible candidates, because its loss seems to correlate with the occurrence of DiGeorge syndrome. Clearly there are other genes that contribute to the behavioral and psychiatric disorders that remain to be identified.
The diagnosis of this condition may be suspected on clinical grounds but can be established only by detection of the deletion, typically by fluorescence in situ hybridization (FISH) (see
Fig. 7.38B http://ebooksmedicine.net
Downsyndromeisassociatedwithanextracopyofgenesonchromosome21,mostcommonlyduetotrisomy21andlessfrequentlyfromtranslocationofextrachromosomalmaterialfromchromosome21tootherchromosomesorfrommosaicism.
PatientswithDownsyndromehaveseverementalretardation,flatfacialprofile,epicanthicfolds,cardiacmalformations,higherriskofleukemiaandinfections,andprematuredevelopmentofAlzheimerdisease.
Deletionofgenesatchromosomallocus22q11.2givesrisetomalformationsaffectingtheface,heart,thymus,andparathyroids.Theresultingdisordersarerecognizedas(1)DiGeorgesyndrome(thymichypoplasiawithdiminishedT-cellimmunityandparathyroidhypoplasiawithhypocalcemia),and(2)velocardiofacialsyndrome(congenitalheartdiseaseinvolvingoutflowtracts,facialdysmorphism,anddevelopmentaldelay).