A number sign (#) is used with this entry because of evidence that autosomal dominant primary microcephaly-26 (MCPH26) is caused by heterozygous mutation in the LMNB1 gene (150340) on chromosome 5q23.

Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020).

For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Cristofoli et al. (2020) reported 7 patients from 5 unrelated families of various ethnic origins with primary microcephaly. The patients, who ranged from 2 to 11 years of age, had microcephaly (-3.6 SD to -12 SD) and global developmental delay. The severity was highly variable: one patient (P2) and her similarly affected mother had the mildest phenotype with head circumferences measuring -3.6 and -2.5 SD, respectively. The patient walked at age 2 years, had slow language acquisition, and followed special education. She had no brain imaging anomalies besides microcephaly. The mother had a history of learning difficulties. The most severely affected patients had poor overall growth with short stature, feeding problems requiring tube feeding, axial hypotonia, spastic tetraparesis, inability to walk, neurogenic scoliosis, severe intellectual disability with absent language, cortical visual impairment, and seizures. Brain imaging in the more severely affected patients showed a simplified gyral pattern, pachygyria, lissencephaly, and dysgenesis of the corpus callosum. Some patients had nonspecific dysmorphic facial features, including long philtrum, short nose, prominent nasal root, bitemporal narrowing, upslanting palpebral fissures, long palpebral fissures, and gingival hypertrophy.

Parry et al. (2021) reported 7 unrelated patients (P1-P3, P9-P11, and P13) with MCPH26 confirmed by genetic analysis. The patients were ascertained from 2 large cohorts (the DDD study and the 100,000 Genomes Project) of individuals with microcephaly who underwent exome sequencing. The patients had global developmental delay with variably impaired intellectual development, poor or absent language, and delayed walking or inability to walk. Some had failure to thrive with poor feeding. Three patients had seizures and 2 had hypothyroidism. Nonspecific dysmorphic features were sometimes observed: these included sloping forehead, upslanting palpebral fissures, hypertelorism, depressed and broad nasal bridge, pointed chin, kyphosis, and overlapping toes. Brain imaging was normal in some patients, but in others showed enlarged ventricles, simplified gyral pattern, or aplasia of the corpus callosum.

The transmission pattern of MCPH26 in 2 families reported by Cristofoli et al. (2020) was consistent with autosomal dominant inheritance; heterozygous mutations in the LMNB1 gene identified in other patients with the disorder occurred de novo.

In 7 patients from 5 unrelated families with MCPH26, Cristofoli et al. (2020) identified heterozygous mutations in the LMNB1 gene (150340.0002-150340.0006). The mutations were found by whole-exome sequencing or microarray analysis and confirmed by Sanger sequencing. The mutations occurred de novo in 3 patients, whereas 1 was inherited from a mildly affected mother, and in 3 sibs were inherited from an unaffected father who was mosaic for the mutation. There was 1 intragenic deletion, 1 splice site mutation, and 3 missense variants affecting highly conserved residues. In vitro functional expression studies of the 3 missense variants showed that they caused variable abnormalities of the nuclear lamina and/or misshapen nuclei. One was associated with decreased protein expression, and the others caused mislocalization of LMNB1 to the cytoplasm. However, mitotic spindle formation and segregation did not appear to be affected. The authors postulated a dominant-negative effect.

In 7 unrelated patients (P1-P3, P9-P11, P13) with MCPH26, Parry et al. (2021) identified heterozygous mutations in the LMNB1 gene (see, e.g., 150340.0004 and 150340.0007). There were 2 recurrent missense mutations and an in-frame deletion; none were present in the gnomAD database. The mutations occurred de novo in all patients for whom parental material was available. The location of the mutations predicted interference with dimer or filament assembly, and in vitro functional expression studies in cells transfected with the mutations showed that they caused abnormal LMNB1 nuclear aggregates and an altered nuclear shape. Parry et al. (2021) postulated that the mutations may alter the properties of lamin filaments, resulting in fragile nuclei that are susceptible to the mechanical stresses of nuclear and neuronal migration, leading to increased cell death during brain development.