A number sign (#) is used with this entry because of evidence that developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is caused by heterozygous mutation in the SRCAP gene (611421) on chromosome 16p11.

Heterozygous mutation in the SRCAP gene also causes Floating-Harbor syndrome (FLHS; 136140). Patients with FLHS have truncating mutations within a specific region of the gene, namely exons 33 and 34, whereas patients with DEHMBA have truncating mutations either proximal or distal to the 'FLHS region' of the SRCAP gene.

Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is an early-onset neurodevelopmental disorder characterized by these features. Affected individuals also have nonspecific and variable dysmorphic facial features that do not constitute a recognizable gestalt. Although the disorder is caused by truncating mutations in the SRCAP gene as is FLHS, the DEHMBA phenotype is clinically distinguishable from FLHS by the lack of short stature, brachydactyly, and delayed bone age, as well as absence of a specific facial appearance. There are some overlapping features between the 2 disorders, mainly impaired intellectual development and speech delay (summary by Rots et al., 2021).

Rots et al. (2021) reported 33 patients with a neurodevelopmental disorder characterized mainly by global developmental delay with or without intellectual disability, behavioral and psychiatric problems, nonspecific facial features, musculoskeletal issues, and hypotonia. The patients were ascertained through international collaborative efforts after genetic analysis identified de novo heterozygous truncating mutations in the SRCAP gene that were proximal to the FLHS region (in 28 patients) or distal to the FLSH region (5 patients). None of the patients had a clinical diagnosis of FLHS, and the features were considered to be distinct from FHLS. Most notable were the absence of short stature and delayed bone age, lack of broad thumbs/fingertips and brachydactyly, and absence of the characteristic dysmorphic facial gestalt that is usually associated with FLHS. The patients with DEHMBA had speech and motor delay with hypotonia. Most had mildly impaired intellectual development and required special schooling, although a few had more severely impaired cognition. Behavioral abnormalities included autism spectrum disorder (in about half of patients), challenging behavior, anger, anxiety, ADHD, tics, Tourette syndrome (in 4), and psychosis (in 4). Skeletal anomalies included joint hypermobility, chronic musculoskeletal pain, scoliosis, and pectus defects; short stature and brachydactyly were not present. Rare patients had seizures (in 3), genitourinary abnormalities (in 3), or gastroesophageal reflux in infancy. Dysmorphic facial features were variable and nonspecific. Many had a long face and long philtrum, prominent forehead, thin vermilion upper lip with everted lower vermilion, and wide mouth. Other features included narrow palpebral fissures, epicanthal folds, periorbital fullness, wide nasal bridge, prominent ears, and retro- or prognathia. About 40% of patients had myopia or hypermetropia. Use of a facial recognition algorithm also indicated that patients with DEHMBA could not be discriminated from controls; they did not have a unifying facial gestalt, and the features were distinct from those of FLHS. Those with a mutation proximal to the FLHS region did not differ significantly from those with a mutation distal to the FLHS region.

The heterozygous mutations in the SRCAP gene that were identified in patients with DEHMBA by Rots et al. (2021) occurred de novo.

In 33 unrelated patients with DEHMBA, Rots et al. (2021) identified heterozygous truncating mutations in the SRCAP gene (see, e.g., 611421.0008-611421.0011). The mutations, which were found by exome sequencing, occurred de novo in those from whom parental DNA was available, which was the majority of patients. None were present in the gnomAD database. The mutations occurred proximal to the FLHS region in 28 individuals and distal to the FLHS region in 5 individuals. None of the mutations were recurrent. DNA methylation (DNAm) analysis of 8 patients with FLHS, 9 with proximal SRCAP variants, and 5 with distal SRCAP variants showed distinct methylation signatures, suggesting diverse pathogenicity of these variants. Rots et al. (2021) hypothesized that truncating mutations proximal to the FLHS region may be subject to nonsense-mediated mRNA decay and cause haploinsufficiency.