Intellectual Developmental Disorder With Dysmorphic Facies And Behavioral Abnormalities

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) is caused by heterozygous mutation in the FBXO11 gene (607871) on chromosome 2p16.

Clinical Features

Gregor et al. (2018) reported 18 unrelated patients, ranging in age from 1 to 29 years, with a syndromic intellectual developmental disorder associated with de novo heterozygous mutations in the FBXO11 gene. The patients were identified through collaborative efforts of research groups with exome sequencing data from patients with developmental delay. The severity and additional manifestations varied among the patients. All patients had delayed psychomotor development; intellectual disability ranged from mild to moderate in most patients, with only 4 patients being classified as having severe to profound deficits. Similarly, speech was usually delayed, and a few patients were nonverbal. Patients were able to attend either special or mainstream schools with additional support. Most patients had mildly delayed walking by 2 years, although a few did not achieve independent ambulation until age 5 or 6 years. Only 5 patients had seizures, and the severity ranged from epileptic encephalopathy to a single seizure. Additional common features included short stature, strabismus, hypermetropia, hypotonia, sleeping difficulties, and distal mild skeletal anomalies, such as small hands and feet, tapering fingers, clinodactyly, sandal gap, and flat feet. Most patients had a variety of behavioral abnormalities, such as poor social interaction, autistic features, stereotypic movements, hyperactivity, short attention span, and aggressive outbursts. Dysmorphic features were common, but there was not a distinctive gestalt. Some of these features included small head circumference, downslanting palpebral fissures, strabismus, deep-set eyes, hypertelorism, low-set ears, long philtrum, long eyelashes, narrow mouth, everted lower lip, and long face.

Fritzen et al. (2018) reported 2 unrelated boys with IDDFBA. One patient was a 14-year-old boy with global developmental delay apparent during his first years of life. He started walking at the age of 20 months and spoke his first sentences at age 4. He had hyperactivity, impatience, difficulties in focusing his attention, and a hyperkinetic disorder. Dysmorphic features included small head circumference, upslanting palpebral fissures, small and posteriorly rotated ears, and small hands with short fingers and toes. The other patient was a 3-year-old boy with intrauterine growth retardation, hypotonia, delayed psychomotor development, strabismus, short stature, and restless behavior. He also had plagiocephaly, a high forehead, a high frontal hairline, deep-set eyes, a broad tip of the nose with small alae, long philtrum, tented upper lip vermilion, downturned corners of the mouth, and full lips. He had hypospadias and his toenails were small and deep-set.

Jansen et al. (2019) reported 24 individuals with borderline to severely impaired intellectual development, 16 of whom also had behavioral problems, including autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, and aggression. More than half of the patients had hypotonia and a few had epilepsy. Brain imaging was performed in 17 patients and enlarged ventricles were seen in 6 of them. Three patients had additional brain anomalies, including hypoplasia of the anterior pituitary, bilateral hippocampal malformations and borderline large cerebellum, Chiari 2 malformation, and syringomyelia. Obesity was observed in 7 individuals. The most consistent facial features were a high broad forehead, long palpebral fissures, and a thin upper lip with broad space between the paramedian peaks. Minor hand abnormalities (e.g., brachydactyly or tapering fingers) were seen in half of the patients, and 8 patients had hyperlaxity of the joints. Gastrointestinal problems such as vomiting and feeding difficulties were reported in 11 patients and vision problems were reported in 9 patients.

Molecular Genetics

In 18 unrelated patients with IDDFBA, Gregor et al. (2018) reported de novo heterozygous mutations in the FBXO11 gene (see, e.g., 607871.0001-607871.0005). The patients were identified through collaborative efforts of research groups with exome sequencing data from patients with developmental delay. There were 10 nonsense, splice site, or frameshift mutations (likely gene-disrupting, LGD) and 8 missense mutations at highly conserved residues distributed throughout the gene. Two additional patients carried larger deletions, including 1 patient with deletion of additional genes. None of the variants were present in the ExAC or gnomAD databases. Functional studies of the variants and studies of patient cells were not performed, but the presence of LGDs and molecular modeling of the missense mutations predicted that all would result in a loss of function and haploinsufficiency. One of the patients (patient 18) was originally reported by Martinez et al. (2017) as part of a large study of 92 patients with intellectual disability who underwent next-generation sequencing of a gene panel.

Fritzen et al. (2018) reported 2 unrelated patients with IDDFBA associated with de novo heterozygous mutations in the FBXO11 gene (607871.0005 and 607871.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function.

Jansen et al. (2019) identified 24 individuals with impaired intellectual development with behavior problems and dysmorphic features who had heterozygosity for de novo variant in or partial deletion of the FBXO11 gene. Among the 24 individuals, 22 variants were identified by next-generation sequencing, including 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to premature termination or degraded transcript. The remaining 2 variants were identified using chromosome microarray and consisted of partial deletions of FBXO11: a 21-kb intragenic deletion of exons 2-13 and a 170-kb deletion disrupting the 3-prime end of FBXO11 by deleting exons 12-24.

Population Genetics

Based on the number of patients identified with FBXO11 variants among a total cohort of over 14,000 patients studied, Jansen et al. (2019) estimated the frequency of a de novo disease-causing variant in FBXO11 in an unbiased cohort of individuals with intellectual disability and autism spectrum disorder to be in the range of 1:500-1:1000.