Microcephaly, Growth Restriction, And Increased Sister Chromatid Exchange 2

A number sign (#) is used with this entry because of evidence that microcephaly, growth restriction, and increased sister chromatid exchange-2 (MGRISCE2) is caused by homozygous or compound heterozygous mutation in the TOP3A gene (601243) on chromosome 17p11.

Description

MGRISCE2 is an autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies. The disorder results from defective DNA decatenation. The pathogenesis of the disorder is similar to that of Bloom syndrome (BLM; 210900), but patients with mutations in the TOP3A gene do not have a malar rash (summary by Martin et al., 2018).

For a discussion of genetic heterogeneity of MGRISCE, see Bloom syndrome (BLM; MGRISCE1; 210900)

Clinical Features

Martin et al. (2018) reported 10 patients from 7 unrelated families with growth failure. The patients, who ranged in age from 5 months to 15 years, had intrauterine growth retardation, low birth growth parameters, and poor postnatal growth (weight between -2.7 and -7.5 SD, height between -2.7 to -5.8 SD), as well as microcephaly -2.3 to -5.7 SD. Multiple cafe-au-lait patches were observed in some patients, but none had a malar rash. Several patients had dilated cardiomyopathy, including 2 who died of the heart disease. Additional less common features included mild developmental delay (4 patients), decreased subcutaneous fat (3 patients), recurrent infections (3 patients), and gastroesophageal reflux (2 patients). Photographs of some of the patients provided in the article suggested dysmorphic facial features, including frontal bossing and progeroid features in some. Skeletal muscle biopsy from 1 patient showed 87% mitochondrial DNA depletion; this measurement was not available from the other patients. None of the patients had malignancies, but Martin et al. (2018) noted that they were still young at the time of report.

Inheritance

The transmission pattern of MGRISCE2 in the families reported by Martin et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 10 patients from 7 unrelated families with MGRISCE2, Martin et al. (2018) identified biallelic mutations in the TOP3A gene (see, e.g., 601243.0001-601243.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All except 1 were predicted to result in a frameshift and premature termination, often associated with nonsense-mediated mRNA decay and consistent with a loss of function. One patient (patient 5) was compound heterozygous for a missense mutation (A176V) and a frameshift mutation. Cells derived from several patients showed decreased amounts of TOP3A protein. Patient cells showed significantly increased (3- to 6-fold) more sister chromatid exchanges (SCEs) compared to controls, suggesting extensive crossover recombination. Cells from 1 patient showed chromosome segregation defects during mitosis, with increased chromatin bridges and lagging chromatin and chromosomes, as well as postmitotic defects, such as increased micronuclei and abnormal nuclear bodies. The findings were consistent with an overall accumulation of DNA damage and genomic instability that could impair cell viability during development, causing microcephaly and growth restriction.