Shukla-Vernon Syndrome

A number sign (#) is used with this entry because of evidence that Shukla-Vernon syndrome (SHUVER) is caused by hemizygous mutation in the BCORL1 gene (300688) on chromosome Xq25.

Description

Shukla-Vernon syndrome (SHUVER) is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, and behavioral abnormalities, including autism spectrum disorder and ADHD. Dysmorphic features are common and may include tall forehead, downslanting palpebral fissures, and tapering fingers. Some patients may have seizures and/or cerebellar atrophy on brain imaging. Carrier mothers may have mild manifestations, including learning disabilities (summary by Shukla et al., 2019).

Clinical Features

Schuurs-Hoeijmakers et al. (2013) reported 2 Dutch brothers, born of unrelated parents, with hypotonia, coarse facial features, and severe intellectual disability. The patients did not have seizures.

Shukla et al. (2019) reported 5 boys from 3 unrelated families with a similar neurodevelopmental disorder. The 2 unrelated boys, 15 and 7 years of age, were identified at a genetics clinic in the U.S. They had mild developmental delay and hypotonia apparent from infancy, although both learned to walk and speak, and both were diagnosed with autism spectrum disorder and ADHD. Only 1 was reported to have mild intellectual disability. Neither had seizures, and brain imaging was not performed. Three brothers from an Indian family had a more severe phenotype with poor overall growth, early-onset seizures associated with EEG abnormalities, and cerebellar atrophy on brain imaging. These sibs had severely impaired intellectual development with delayed walking and speech; 1 was nonverbal at age 15 years. All had been diagnosed with autism spectrum disorder. All patients had variable, but overlapping, dysmorphic features, including long face, tall forehead, hypertelorism, downslanting palpebral fissures, broad base of nose, thick vermilion, dysmorphic ears, strabismus or exotropia, and long fingers.

Inheritance

The transmission pattern of SHUVER in the families reported by Shukla et al. (2019) was consistent with X-linked recessive inheritance, although some carrier females demonstrated mild manifestations.

Molecular Genetics

In 2 Dutch brothers (family W07-1601), born of unrelated parents, with SHUVER, Schuurs-Hoeijmakers et al. (2013) identified a hemizygous missense mutation in the BCORL1 gene (N820S; 300688.0001). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. Schuurs-Hoeijmakers et al. (2013) noted that the BCORL1 gene is expressed in the brain or in neuronal tissue. No functional studies of the variant were performed. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing.

In 5 boys from 3 families with SHUVER, Shukla et al. (2019) identified hemizygous missense mutations in the BCORL1 gene (300688.0002-300688.0004). The mutations, which were found by whole-exome sequencing, were inherited from mothers who were unaffected or had mild manifestations, such as learning disabilities. Functional studies of the variants and studies of patient cells were not performed.