Rett Syndrome, Angelman Syndrome and Variant Syndromes Panel

Rett syndrome is a neurodevelopmental disorder that is one of the most frequent causes of intellectual disability in females. Rett syndrome patients display normal development during early infancy, but between 6 and 18 months undergo psychomotor regression in which they lose previously acquired skills (Neul et al. 2010. PubMed ID: 21154482; Ehrhart et al. 2016. PubMed ID: 27884167). Other key features of Rett syndrome include loss of language/communication dysfunction, microcephaly, stereotyped hand-wringing motions and seizures. Variations of classic Rett syndrome, termed atypical Rett syndrome or Rett-like syndromes, have been described. Atypical Rett syndrome patients share major clinical features with classic Rett syndrome, but have variable secondary features such as bruxism, impaired sleep, and growth retardation (Neul et al. 2010. PubMed ID: 21154482; Marangi and Zollino. 2015. PubMed ID: 27617128; Vidal et al. 2019. PubMed ID: 31105003; Iwama et al. 2019. PubMed ID: 30842224). The vast majority of patients with Rett syndrome are female. Male patients with pathogenic variants in MECP2 have been reported with non-syndromic intellectual disability, absence of speech, neurodevelopmental delay, and epilepsy (Campos et al. 2007. PubMed ID: 17084570; Schönewolf-Greulich et al. 2016. PubMed ID: 26936630).

Angelman syndrome is a neurodevelopmental disorder characterized by severe intellectual disability, seizure, developmental delay, absent or minimal speech development, ataxic gait and/or tremulousness of the limbs, microcephaly and a unique behavioral phenotype that includes happy demeanor and excessive laughter. Developmental delays are first noted at 3 to 6 months age, but the unique clinical features of the syndrome do not manifest until after age 1 year (Williams et al. 2010. PubMed ID: 20445456; Dagli et al. 2012. PubMed ID: 22670133; Sato. 2017. PubMed ID: 28326016).

This panel covers genes for Rett syndrome, Angleman syndrome and their variant syndromes which share common clinical features (Marangi and Zollino. 2015. PubMed ID: 27617128; Ehrhart et al. 2016. PubMed ID: 27884167; Vidal et al. 2019. PubMed ID: 31105003; Iwama et al. 2019. PubMed ID: 30842224). Genes in this panel are discussed briefly below:

MECP2: For Rett syndrome, the causative gene is MECP2. The syndrome is inherited in X-linked dominant manner.

Other genes in which pathogenic variants cause a similar phenotype to Rett syndrome include: CDKL5, HDAC8, IQSEC2, PDHA1 and WDR45 (X-linked dominant); ARX (X-linked recessive); FOXG1, CAMK2B, GABRA1, GRIN2B, KCNQ2, KIF1A, MEF2C, SCN2A, SCN8A and STXBP1 (autosomal dominant); PPT1 (autosomal recessive).

UBE3A: Angelman syndrome is caused by a deficiency of the imprinted and maternally expressed UBE3A gene. This means only UBE3A pathogenic variants present on the maternal allele cause Angelman syndrome. The molecular mechanisms include: (1) Deletions of the 15q11.2-q13 region, containing UBE3A (65%–70% of cases). (2) Paternal uniparental disomy of chromosome 15 (3%–7% of cases). (3) Imprinting center defects within the 15q11.2-q13 region (2%–5% of cases). (4) Loss of function pathogenic variants in the maternal UBE3A allele (5-10% of cases) (Williams et al. 2010. PubMed ID: 20445456; Dagli et al. 2012. PubMed ID: 22670133; Sadikovic et al. 2014. PubMed ID: 25212744).

Other genes for a differential diagnosis for Angelman syndrome include: SLC9A6 (X-linked recessive); TCF4, MBD5, ZEB2 (autosomal dominant); CNTNAP2 and NRXN1 (autosomal recessive).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Causative point variants in MECP2 are found in 80% of typical Rett syndrome cases and 40% of atypical Rett syndrome cases (Christodoulou and Ho. 2012. PubMed ID: 20301670).

Approximately 10% of Angelman syndrome patients have pathogenic variants in the UBE3A gene (Sadikovic et al. 2014. PubMed ID: 25212744). This panel should be considered for Angelman syndrome patients that have normal methylation analysis of the 15q11.2-q13 region. Methylation analysis is the preferred first test for Angelman syndrome isolated cases. In particular, this panel does not detect imprinting defects, uniparental disomy, certain copy number variants or complex rearrangements involving chromosome 15q11.2-q13 for Angleman.

This panel has genes causative for Rett syndrome, Angelman syndrome and their variant syndromes, therefore, we predict that this panel will have a high sensitivity for identifying a causative gene in these syndromes.

Large deletions or duplications have been reported in ARX, CDKL5, CNTNAP2, FOXG1, GABRA1, GRIN2B, HDAC8, IQSEC2, KCNQ2, KIF1A, MEF2C, NRXN1, PDHA1, PPT1, SCN2A, SCN8A, STXBP1, UBE3A, WDR45, and ZEB2 (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).