FTO-Deficiency Syndrome via the FTO Gene

Intellectual disability (ID) refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities, AAIDD). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in ~1-3% of the population, irrespective of any social class and culture (Kaufman et al. 2010; Vissers et al. 2016). ID and Autism Spectrum Disorders (ASD) are also highly comorbid with each other, suggesting shared etiologies.

FTO-Deficiency Syndrome (also known as Growth Retardation, Developmental Delay, and Facial Dysmorphism) is a rare syndromic from of ID characterized by developmental delay and distinctive dysmorphic features. Other clinical features include: microcephaly, failure to thrive, decreased brain volume, left ventricular hypertrophy, bilateral hearing loss, and in some cases genital anomalies and cleft palate (Daoud et al. 2016; Boissel et al. 2009). Homozygous missense variants within the FTO gene have been identified to segregate with the clinical features of FTO-Deficiency Syndrome in 10 affected individuals from two families.

Intellectual disability is inherited in a multifactorial fashion, with heritability estimates ranging between 15-50% (Larsen et al. 2016; Karam et al. 2015). Approximately 30% more males than females are diagnosed with ID, yet the male-to-female ratio decreases with decreasing IQ (American Psychiatric Association 2000). Co-occurring ASD and ID has a similar male-to-female prevalence ratio of ~4:1 (Christensen et al. 2016). Single nucleotide polymorphisms within the first intron of FTO have also been associated with childhood and adult obesity in multiple human populations and in mouse models (Fawcett et al. 2010; Church et al. 2010).

FTO-Deficiency Syndrome has been reported in individuals with homozygous missense variants in the 2-oxogluterate binding domain of FTO, supporting an autosomal recessive mode of inheritance.

The human FTO gene contains 9 protein-coding exons which encode a 505 amino acid protein. Bacterial and human homologs of FTO are involved in the repair of alkylated DNA and RNA damage from oxidative demethylation. FTO has also been shown to demethylate m⁶A in mRNA, which plays an important role in gene expression, mRNA processing, and transcript localization (Dominissini et al. 2012). In vitro studies of recombinant human FTO protein with and without a reported missense variant reveal a significant impact on the demethylase activity of the protein (Boissel et al. 2009) The FTO gene (fat mass and obesity-associated) encodes a nuclear iron-dependent oxygenase that is part of the AlkB homologue subfamily (Daoud et al. 2016; Boissel et al. 2009). The FTO protein is hypothesized to be critical for normal development of the nervous and cardiovascular systems through gene regulation (Daoud et al. 2016). The FTO gene is apparently ubiquitously expressed, with highest levels of expression observed in the human central nervous system, liver, and various structures of the heart (Boissel et al. 2009).

Genetic variants have been found responsible in 25-50% of ID cases and this percentage increases proportionally with the severity of the phenotype (McLaren and Bryson 1987). To date, a total of 10 homozygous individuals from two families have been reported with missense variants in their FTO gene all presenting with similar clinical features.

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

This test provides full coverage of all coding exons of the FTO gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.