Developmental Disabilities

Nancy J. Carpenter, Kristin May, Benjamin Roa, and Jack Tarleton

Although the classic childhood phenotypes of many developmental disorders have been established for some time, only in the past decade have the genetic etiologies of some of these disorders been identified. Investigations of the molecular basis of these conditions have resulted in the identification of new genes, leading to insights into the function of new proteins and biochemical pathways. In addition, genetic mechanisms previously unknown in humans, such as genomic imprinting, uniparental disomy, expansion of trinucleotide repeats, and facilitation of deletions and duplications by low-copy repeats, were recognized as the causes of some of these conditions.

This chapter reviews the genetic etiologies of several developmental disorders, including the fragile X, Prader-Willi, Angelman, Rett, and Williams syndromes, and disorders due to cryptic unbalanced chromosome rearrangements. The molecular approaches being applied to the diagnosis of these disorders also are reviewed.


Named for its association with a chromosomal fragile site observed in many patients (FRAXA chromosomal locus Xq27.3), fragile X syndrome (FXS) is the most common cause of inherited mental retardation (MR). FXS results from loss or severe reduction of the protein FMRP,encoded by the FMR1 (fragile X mental retardation) gene.1 All patients with FXS have mutations in FMR1, as no mutations leading to FXS have been identified in other genes. Both males and females may be affected with FXS, but females are typically less severely affected. Thus, FXS is considered to be X-linked dominant with reduced penetrance in females.2

The FMR1 gene encompasses 38 kilobases (kb) of genomic DNA and has 17 exons.3 The major FMR1 messenger RNA (mRNA) produced in most tissues is approximately 4kb, although several protein isoforms are generated by alternative splicing toward the 3' end of the mRNA in some tissues. While FMRP can be detected in the nucleus, the majority of the protein associates with translating ribosomes in the cytoplasm, where it acts as a negative translational regulator. FMRP also is known to have a role in neuronal synapse maturation and plasticity. Autopsy samples from FXS patients have shown failure of dendritic spines to assume a normal mature size, shape, and distribution.

The molecular genetics of FMR1 are complex. A repeated trinucleotide sequence, composed primarily of CGG repeats, is located in the untranslated portion of exon 1, ending 69 base pairs upstream of the translational start. Nearly all mutations (>99%) resulting in FXS occur as instability of the trinucleotide repeat,leading to dramatic expansion of the repeat segment (>200 to a few thousand repeats) accompanied by aberrant hypermethylation of CpG dinu-cleotides within the gene (full mutations). Relatively rare deletions and point mutations in FMR1 account for the remaining mutations found in patients with FXS. The mechanism of repeat instability in FMR1 is believed to be DNA polymerase slippage during DNA replication. AGG repeats, spaced at about 10 repeat intervals within the CGG repeat segment, may mitigate potential repeat instability through disruption of higher-order molecular structures formed during DNA replication. These secondary structures contribute to polymerase slippage, and alleles that lack interrupting AGG repeats are at higher risk for expansion.

The FMR1 repeat region is naturally polymorphic, with variation of the CGG repeats in normal (i.e., stably inherited) alleles ranging from 5 to 40 repeats, and the vast majority of individuals in the general population have 20 to 40 repeats. Intermediate repeat alleles containing 41 to 59 repeats occasionally have minor variations of a few repeats when transmitted from parent to child, producing no clinical consequences. However, in rare instances, transmission of intermediate alleles with 55 to 59 repeats may expand into pathological alleles.

Interestingly, FXS occurs strictly through maternal inheritance. Individuals with full mutations may inherit a

Table 6-1. Normal and Pathological FMR1 Allele Types


Repeat Range











Full mutation



Methylation mosaic




Mixed premutation

Full mutation

mutation repeat

and full mutation

may be

size mosaic


similar allele from their mothers or, alternatively, their mothers may have a "premutation" allele. FMR1 alleles with >60 repeats up to approximately 200 repeats are considered premutations because of potential instability. Individuals with premutations do not have typical characteristics associated with FXS but may transmit an unstable repeat,which undergoes extensive repeat expansion. When transmitted by fathers to their daughters, premutations are not dramatically unstable, and as a result full mutations never arise through paternal inheritance.

Hypermethylation of the FMR1 promoter region, along with repeat expansion, results in decreased or completely absent transcription and the concomitant loss of FMRP. Patients with partial methylation of a full mutation (methylation mosaics) may have some FMRP expression, resulting in a less severe phenotype. In addition, patients with a mixture of cells having either a premutation or full mutation (premutation/full mutation size mosaics) frequently are identified during molecular testing. These patients usually have MR but may perform at the lower end of normal intellect (IQ > 70). Because methylation is not an all-or-none phenomenon within FMR1, the FXS phenotype may encompass a spectrum of possible affectations from mild to severe. Table 6-1 summarizes the classification of FMR1 alleles.

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