A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-7 (CSS7) is caused by heterozygous mutation in the DPF2 gene (601671) on chromosome 11q13.

Coffin-Siris syndrome-7 (CSS7) is a neurodevelopmental disorder characterized by global developmental delay with mild to moderate intellectual disability, speech impairment, behavioral abnormalities, poor overall growth, coarse facial features, and hypoplastic fifth toenails (summary by Vasileiou et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Vasileiou et al. (2018) reported 8 unrelated patients with a neurodevelopmental disorder consistent with CSS. The patients, who ranged in age from 3 to 18 years, were ascertained from several collaborative groups. All patients had global developmental delay with borderline, mild, or moderate intellectual disability, delayed speech, mildly delayed walking between 17 and 24 months, and hypoplasia of the fifth toenail. Some individuals had other distal skeletal anomalies, including hypoplasia of other toenails and/or fingernails, brachydactyly, and clinodactyly of the fifth finger. Most patients had coarse facial features and dysmorphic features, including sparse scalp hair, downslanting palpebral fissures, hypertelorism, thick or small alae nasi, short or broad philtrum, large, prominent, low-set and/or posteriorly rotated ears, prominent forehead, broad nose with flat nasal bridge, wide mouth, thin upper lip, thick lower vermilion, thick eyebrows, and delayed dentition or microdontia. Additional more variable features included feeding difficulties in infancy, poor overall growth, hypotonia, hearing impairment, behavioral abnormalities, constipation, recurrent otitis media, hypermetropia, and strabismus. Four patients had congenital heart defects, including septal defects, valvular abnormalities, and persistent foramen ovale. Two patients had sagittal craniosynostosis and 1 had trigonocephaly. Brain imaging performed in 3 patients showed variable mild abnormalities, including right cerebellar hemisphere atrophy, small pituitary gland, and Chiari malformation I, respectively, but none of the patients had abnormalities of the corpus callosum.

The heterozygous mutations in the DPF2 gene that were identified in patients with CSS7 by Vasileiou et al. (2018) occurred de novo.

In 8 unrelated patients with CSS7, Vasileiou et al. (2018) identified 8 different de novo heterozygous mutations in the DPF2 gene (see, e.g., 601671.0001-601671.0005). There were 5 missense mutations, 2 splice site mutations, and 1 frameshift mutation. The missense mutations affected highly conserved residues in the PHD1 or PHD2 finger domains, which are responsible for the recognition of histone modifications. The mutations were close to zinc binding sites, most likely disrupting these sites and the protein structure. In vitro functional expression studies of 3 of the missense mutations (C276F, 601671.0001; C330W, 601671.0002; and R350H, 601671.0003) showed that they resulted in abolished or strongly attenuated binding to certain modified and unmodified H3 histone tails. In addition, expression of the mutations in HEK293 and COS-7 cells resulted in the formation of abnormal aggregate-like structures in the nucleus when expressed alone, and recruited wildtype DPF2 and BRG1 (603254) to the aggregates with coexpressed with those wildtype proteins. Theses findings were consistent with a dominant-negative pathomechanism. Analysis of the 2 splice site mutations and the frameshift mutation suggested that they escape nonsense-mediated mRNA decay, thus precluding haploinsufficiency and also supporting a dominant-negative mechanism. The patients were ascertained from large cohorts of patients with developmental disabilities and through web-based matching programs and collaboration. Six of the patients had additional rare single-nucleotide variants or copy number variants affecting other genes, which were not considered to affect the phenotype. Vasileiou et al. (2018) suggested that the mutations in nucleosome-targeting modules of the DPF2 gene disrupt PHD finger functional cohesion and capacity to recognize H3 histone modifications, leading to misreading from the BAF complex and epigenetic deregulation of gene transcription. The findings confirmed a crucial role of PHD-finger-containing proteins in human neurodevelopmental disorders.