Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) is caused by heterozygous mutation in the BRPF1 gene (602410) on chromosome 3p25.

Description

Intellectual developmental disorder with dysmorphic facies and ptosis is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (summary by Mattioli et al., 2017).

See also chromosome 3p deletion syndrome (613792).

Clinical Features

Yan et al. (2017) reported 10 patients from 9 unrelated families with global developmental delay apparent since infancy, mild to severe intellectual disability, expressive language impairment, and dysmorphic facial features. Five patients had neonatal feeding difficulties. Most patients had hypotonia and delayed gross and fine motor skills with delayed walking. Four patients had overt seizures, 1 had staring spells, and another had an abnormal EEG. Dysmorphic facial features included broad forehead, flat facial profile, round face, broad nasal root, fleshy nose, widely spaced eyes with downslanting palpebral fissures, blepharophimosis, ptosis, short philtrum, small or wide mouth, and abnormal ears. Most patients had joint hypermobility, and 4 had cervical spinal fusion abnormalities. Brain imaging, performed in 7 patients, showed abnormalities in 4, including white matter abnormalities, decreased white matter volume suggesting abnormal myelination, and thin corpus callosum.

Mattioli et al. (2017) reported a large 3-generation family in which 6 individuals had an autosomal dominant syndromic form of mild intellectual disability associated with additional features such as growth retardation, ptosis, and relative microcephaly. The proband, who was in the third generation and the most severely affected patient, had intrauterine growth retardation, clubfeet, and edema on the back of the feet. Soon after birth he showed hypotonia, poor feeding associated with gastroesophageal reflux, and poor overall growth. Dysmorphic features included left ptosis, bilateral epicanthus, anteverted nostrils, round face, long philtrum, small and round ears, and unilateral cryptorchidism. He had delayed psychomotor development with delayed walking at age 30 months and delayed speech. Brain imaging in this patient showed agenesis of the corpus callosum. A sib and a first cousin were similarly affected, although brain imaging performed in 1 was normal. The proband's mother had mild intellectual disability, short stature, bilateral ptosis, brachymetacarpia, and similar facial dysmorphism. Familial history revealed that her deceased mother and 2 sisters had the same phenotype. Subsequently, 4 unrelated boys with de novo heterozygous BRPF1 mutations were identified through the GeneMatcher exchange database. These patients, who ranged in age from 3 to 12 years, had delayed psychomotor development, with mild to moderate intellectual disability, delayed walking, speech delay, and ptosis and/or blepharophimosis. Dysmorphic features included round face, downslanting palpebral fissures, temporal narrowing, and downturned mouth. Additional more variable features included hypotonia, short stature, microcephaly, strabismus, and camptodactyly. Two patients had seizures.

Molecular Genetics

In 10 patients from 9 unrelated families with IDDDFP, Yan et al. (2017) identified heterozygous mutations in the BRPF1 gene (see, e.g., 602410.0001-602410.0005). One mutation was a missense mutation, and all the others were nonsense or frameshift mutations leading to C-terminal truncations of the protein that differed in which structural domains were deleted. Functional assays showed that the resulting BRPF1 variants were pathogenic and impaired acetylation of histone H3 at lysine 23, although they acted through different mechanisms. Mutations that resulted in deletion of domains important for binding to KAT6A (601408), KAT6B (605880), and/or ING5 (608525) and MEAF6 (611001) (see, e.g., 602410.0002 and 602410.0003) were unable to form tetrameric complexes and had reduced ability to stimulate acetyltransferase activity, whereas mutations that occurred distal to these functional domains (see, e.g., 602410.0004) retained the ability to form complexes and had normal acetyltransferase activity, but lacked the PWWP domain, which binds to trimethylated histone H3. The mutations also altered subcellular localization compared to wildtype, again through different mechanisms. The findings suggested that BRPF1 haploinsufficiency, resulting in decreased H3K23 acetylation and deregulation of epigenetic and developmental programs, is the pathogenic mechanism underlying the disorder.

In 5 affected members of a 3-generation family with IDDDFP, Mattioli et al. (2017) identified a heterozygous frameshift mutation in the BRPF1 gene (602410.0006). The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutant protein was able to bind KAT6A, but unable to bind ING5 and MEAF6. Studies of HeLa cells transfected with the mutation showed that the truncated variant failed to stimulate K23 acetylation of histone H3. The mutant protein also showed aberrant intracellular localization. Subsequently, 4 unrelated boys with de novo heterozygous BRPF1 mutations and a phenotype consistent with IDDDFP were identified through the GeneMatcher exchange database (602410.0007-602410.0010). Three of these mutations were truncating mutations and 1 was a missense mutation. Functional studies of these variants were not performed.

Animal Model

Yan et al. (2017) found defective H3K23 acetylation in thymus and spleen protein extracts of transgenic mice with knockdown of Brpf1 specifically in hematopoietic cells. Similar defects were present in dorsal cortex extracts of forebrain-specific Brpf1-knockout mice and protein extracts of epiblast-specific Brpf1-knockout mouse embryos. H3K23 acetylation was not detectable in Brpf1-null mouse embryonic fibroblasts. Heterozygous mutant embryos also showed reduced H3K23 acetylation.