A number sign (#) is used with this entry because of evidence that Beck-Fahrner syndrome (BEFAHRS) is caused by homozygous, compound heterozygous, or heterozygous mutation in the TET3 gene (613555) on chromosome 2p13.

Beck-Fahrner syndrome (BEFAHRS) is a developmental disorder characterized by global developmental delay with variably impaired intellectual development. Affected individuals often have behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD), as well as learning disabilities. Most patients have hypotonia and dysmorphic facies. Some may have growth abnormalities, including overgrowth or poor growth, poor feeding, and rarely, seizures. Although both monoallelic and biallelic mutations have been reported, some heterozygous carriers in autosomal recessive families may have milder symptoms; thus, both groups are included in this entry (summary by Beck et al., 2020).

Autosomal Recessive BEFAHRS

Beck et al. (2020) reported 5 patients from 3 unrelated families with a similar neurologic disorder with variable severity. Two unrelated patients were children, and 3 sibs, born of consanguineous parents (family 3), were in their twenties. The patients had global developmental delay, hypotonia, mildly delayed walking, and poor or absent speech and language. Intellectual disability ranged from mild to moderate. At age 7 years, the least severely affected patient (patient 1) had low average IQ with dyslexia and dyscalculia, as well as behavioral anomalies, including ADHD, obsessive-compulsive disorder (OCD), anxiety, and autistic features with reserved social maturation. At age 3 years, the most severely affected patient (patient 2) was unable walk or speak, had seizures, and was tube-fed. Common dysmorphic features among these patients included tall or broad forehead, long face, smooth philtrum, epicanthal folds, thick eyebrows, hypotonic face or open mouth, protruding ears, and short nose. Patient 1 had macrosomic features, with growth acceleration in early childhood and macrocephaly (greater than +2 SD), whereas the 3 sibs had relatively poor growth trending toward microcephaly (-2 SD). Five of the 6 parents of these patients, all of whom were heterozygous mutation carriers, had milder similar behavioral or psychiatric features, including anxiety, learning difficulties, ADHD, and depression, lending credibility to the putative adverse effect of a heterozygous TET3 mutation (see below).

Autosomal Dominant BEFAHRS

Beck et al. (2020) reported 4 unrelated males and a father-son duo with variable global developmental delay and growth abnormalities. The probands ranged from 11 months to 11 years of age, and the affected father was 56. Three patients had a large head circumference (about +2 SD), and most had variable dysmorphic features similar to those observed in patients with recessive BEFAHRS: these included brachycephaly, tall forehead, long face, short nose, and long philtrum; 2 had a high-arched palate. Three patients had hypotonia and abnormal movements, such as myoclonus, dysmetria, and dystonia. At age 18 months, the most severely affected patient (family 6) had infantile seizures, poor eye contact, no head control, inability to sit or roll over, feeding difficulties with failure to thrive, hip dysplasia, nystagmus, strabismus, and ptosis. At age 10 years, the least severely affected patient (family 8) had ADHD, autism spectrum disorder, anxiety, and impaired language, but was able to attend a special school and had a non-verbal IQ of 84; this patient was not dysmorphic.

The transmission pattern of BEFAHRS in the families reported by Beck et al. (2020) was consistent with either autosomal recessive or autosomal dominant inheritance. Many heterozygous carrier parents of the patients with autosomal recessive inheritance showed similar, but milder, features.

In 5 patients from 3 unrelated families (families 1-3) with autosomal recessive BEFAHRS, Beck et al. (2020) identified homozygous or compound heterozygous missense mutations in the TET3 gene (613555.0001-613555.0005) that segregated with the disorder in the families. All but 1 mutation (R752C) occurred at highly conserved residues in the catalytic domain and resulted in decreased TET3 catalytic activity as measured in vitro by 5-hydroxymethylcytosine (5hmC) production in HEK293 cells; the findings indicated that most of the mutations were hypomorphic. All but 1 of the 5 patients were female. Five of the 6 parents, who were heterozygous mutation carriers, showed similar but milder symptoms. Beck et al. (2020) also reported 4 additional unrelated male patients (families 4, 5, 6, and 8) and a father-son duo (family 7) with autosomal dominant BEFAHRS who carried heterozygous TET3 mutations (see, e.g., 613555.0006-613555.0009). Three of the 5 heterozygous mutations were predicted to result in a nonsense or frameshift mutation, suggesting a loss-of-function effect with haploinsufficiency. However, 2 of these mutations occurred in the last exon, raising the possibility that a truncated protein could be produced and have a dominant-negative effect. The 2 remaining patients carried heterozygous missense variants. Functional studies of the heterozygous variants and studies of patient cells were not performed. All patients, who were ascertained through the GeneMatcher program, underwent exome sequencing with Sanger confirmation in the respective laboratories. None of the variants were found in the gnomAD database except R752C. Nonsense and frameshift mutations were observed only in the heterozygous state, suggesting that some residual TET3 activity is required for viability. The findings also suggested a dose-dependent mechanism, such that if TET3 activity falls below a certain threshold, developmental phenotypes will result, regardless of whether reduced TET3 activity is caused by heterozygous loss-of-function alleles or by biallelic hypomorphic missense alleles. Beck et al. (2020) noted that all but 1 of the patients with biallelic mutations were female, whereas all patients with heterozygous mutations were male, suggesting the possibility of sex-specific differences.