Pilarowski-Bjornsson Syndrome

A number sign (#) is used with this entry because of evidence that Pilarowski-Bjornsson syndrome (PILBOS) is caused by heterozygous mutation in the CHD1 gene (602118) on chromosome 5q.

Description

Pilarowski-Bjornsson syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed development, intellectual disability, often with autistic features, speech apraxia, and mild dysmorphic features. Some patients may have seizures. The phenotype is somewhat variable (summary by Pilarowski et al., 2018).

Clinical Features

Pilarowski et al. (2018) reported 6 girls with a neurodevelopmental disorder and heterozygous missense mutations in the CHD1 gene. The patients were identified through whole-exome sequencing studies and collaboration with other researchers through the GeneMatcher database. Two of the girls were sisters conceived by separate in vitro fertilization cycles from an egg donor for whom genetic data were not available. One of the girls had biallelic, likely pathogenic mutations in the WDR62 gene (613583), and she was not studied further. All 5 patients with specific missense CHD1 mutations had developmental delay and hypotonia, including a 10-year-old girl with developmental regression. Four patients, aged 4 to 10 years, had speech apraxia, 3 had autism with stereotypies, and 5 had seizures or abnormal EEG. The youngest child was 7 months old. Two patients had persistent intellectual disability, and one 5-year-old girl did not have intellectual disability; information on intellectual ability in the 2 other girls was not available. Two patients showed postnatal growth retardation. Dysmorphic features, which were also variable, included macrocephaly, depressed midface, pointed chin, translucent skin, almond-shaped eyes, downslanting palpebral fissures, periorbital fullness, and flared eyebrows. Two patients had mild immune defects.

Molecular Genetics

In 5 unrelated girls with PILBOS, Pilarowski et al. (2018) identified heterozygous missense mutations in the CHD1 gene (see, e.g., 602118.0001-602118.0004). They identified a heterozygous mutation in CHD1 in another girl with a neurodevelopmental disorder, but she also carried biallelic, likely pathogenic mutations in the WDR62 gene (613583) and was therefore not studied further. The 5 remaining patients all had mutations affecting loss of an arginine, and several of the mutations were located in structurally important regions. Cells derived from one of the patients showed a global increase of a closed chromatin modification compared to controls, suggesting that the mutation had functional effects. In vitro functional studies and studies of patient cells were not performed in the other patients. The authors identified 3 previously described patients in large surveys of individuals with autism who had de novo missense (L1016V and R1203Q) and nonsense (Leu1517fsTer) mutations in the CHD1 gene; however, the phenotypic information provided in these reports was limited. An additional patient with a deletion encompassing the RGMB gene (612687) and most of the CHD1 gene had been reported, but this child did not have neurodevelopmental abnormalities. Pilarowski et al. (2018) concluded that missense mutations in the CHD1 gene may cause neurodevelopmental defects through a dominant-negative effect rather than through haploinsufficiency.