Microcephaly, Short Stature, And Limb Abnormalities

A number sign (#) is used with this entry because of evidence that microcephaly, short stature, and limb abnormalities (MISSLA) is caused by homozygous or compound heterozygous mutation in the DONSON gene (611428) on chromosome 21q22.

Biallelic mutation in the DONSON gene can also cause microcephaly-micromelia syndrome (251230), a more severe disorder that usually results in intrauterine or perinatal death.

Description

MISSLA is an autosomal recessive disorder characterized by intrauterine growth retardation, microcephaly, variable short stature, and limb abnormalities mainly affecting the upper limb and radial ray. Affected individuals typically have mild intellectual disability, but may have normal development (summary by Reynolds et al., 2017).

Clinical Features

Reynolds et al. (2017) reported 27 individuals from 20 families with microcephaly and variable short stature. The patients ranged from infancy to the teenage years. Most of the patients had intrauterine growth retardation affecting all parameters, and all continued to have poor growth with short stature (-1.2 SD to -4 SD, although 1 patient had stature of -8.4 SD) and microcephaly (-2.4 to -10.7 SD). Skeletal features included delayed bone age and abnormalities mainly of the upper limbs, including fifth finger clinodactyly, dysplasia or hypoplasia of the radius and thumbs, radioulnar synostosis, elbow subluxation, short metacarpals, and brachydactyly. Several patients had mesomelia, rib abnormalities, and/or absent patella. Most had variable and inconsistent additional features, such as dysmorphic facies with beaked nose and upslanting palpebral fissures and pigmentary abnormalities. Brain imaging of several patients showed a reduction in cerebral cortical size with decreased gyral folding. Cognitive development was mildly impaired, although some patients had normal development. One of the families, previously described by Milner et al. (1993), had 3 sibs, born of consanguineous Palestinian parents, with microcephaly, short stature, slow growth, beaked nose, micrognathia, skin pigmentation abnormalities, and forearm and thumb dysplasia.

Inheritance

The transmission pattern of MISSLA in the families reported by Reynolds et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 27 patients from 20 families with MISSLA, Reynolds et al. (2017) identified homozygous or compound heterozygous mutations in the DONSON gene (see, e.g., 611428.0001-611428.0007). The families were of various ethnic origins, including European, Indian, Saudi Arabian, South African, Palestinian, and Turkish, and several families were consanguineous. The mutations were found by a combination of whole-exome sequencing and Sanger sequencing of affected families or individuals and direct sequencing of a cohort of 230 patients with a similar phenotype. All variants segregated with the disorder in the families and were present at a frequency of less than 0.5% in the ExAC database. Mutation types included nonsense, missense, splice site, frameshift, and in-frame deletions, but none of the patients had biallelic nonsense or frameshift mutations, suggesting that the missense mutations were hypomorphic and likely resulted in a partial loss of function. In vitro functional expression studies and studies of patient cells showed that the mutations resulted in decreased protein levels or altered subcellular localization, consistent with a loss of function. Patient cells and cells with depletion of DONSON showed higher levels of spontaneous fork asymmetry and fork stalling compared to controls, indicating impaired stability of the DNA replication fork. The findings suggested defective DNA replication as the mechanism underlying the disease phenotype.