Biallelic SEMA3A defects cause a novel type of syndromic short stature

Abstract

Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock‐out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in‐frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT‐PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT‐PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A. © 2013 Wiley Periodicals, Inc.

A recognizable type of syndromic short stature with arthrogryposis caused by bi‐allelic SEMA3A loss‐of‐function variants

“…This variant was not listed in dbSNP, ESP, and EXAC databases and segregates with disease in the family (Figures S1–S3). This is the second instance of bi‐allelic loss‐of‐function variants in SEMA3A , identified in each case with a particular MCA pattern, postnatal short stature, and delayed motor development. The most distinguishing features of this condition are skeletal anomalies of the thorax, camptodactyly, and symptoms of hypogonadotropic hypogonadism in pre‐pubertal boys.…”

“…Sema3a knockout mice differ from the patients by early death from heart failure because of a hypertrophic right ventricle, by abnormal cortical and olfactory architecture, and microcephaly . Phenotypic differences between the first reported patient and Sema3a knockout mice might be explained by residual SEMA3A expression or phenotypic differences between patients and mice might be explained by redundant function of different semaphorins in humans. Altogether, SEMA3A deficiency might well account for the distal arthrogryposis, muscular hypotonia, skeletal abnormalities, and symptoms of hypogonadotropic hypogonadism in patients, that is, bi‐allelic SEMA3A variants cause a syndromic form of postnatal short stature.…”

“…Recently, bi‐allelic loss‐of‐function variants in the SEMA3A gene were identified in a single patient, who presented with postnatal short stature and relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies. This patient presented with a novel autosomal recessive syndrome . We report here on another patient with bi‐allelic loss‐of‐function variants in SEMA3A .…”

“…This patient presented with a novel autosomal recessive syndrome. 5 We report here on another patient with bi-allelic loss-of-function variants in SEMA3A. This male patient presents with a highly similar pattern of multiple congenital anomalies (MCA) and postnatal short stature.…”

Semaphorins

“…Taken together, Sema3A not only inhibits RANKL-induced osteoclast differentiation, but also activates osteoblast differentiation (Fig. Hofmann et al recently reported that the biallelic mutations in the SEMA3A gene (a combination of a nonsense mutation in exon 1 and a splice site mutation in exon 9) resulted in a novel disorder characterized by skeletal abnormalities, including postnatal short stature, barrel thorax, funnel chest, and flattened vertebrae of the upper thoracic region, along with multiple minor congenital anomalies (Hofmann et al 2013). The importance of Sema3A signaling in bone is supported by the finding that polymorphisms in PLXNA2 (encoding Plexin-A2, which is a member of the type A plexins and a component of the receptor complex for Sema3A), are associated with low bone mineral density and an increased risk of bone fracture in postmenopausal women of a Korean cohort (Hwang et al 2006).…”