Meier-Gorlin Syndrome 7

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-7 (MGORS7) is caused by homozygous or compound heterozygous mutation in the CDC45 gene (603465) on chromosome 22q11.

For a general phenotypic description and a discussion of genetic heterogeneity of Meier-Gorlin syndrome, see 224690.

Fenwick et al. (2016) studied 15 patients from 12 families with biallelic mutations in the CDC45 gene whose features ranged from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. There were 10 patients from 8 families who presented with the classic triad of Meier-Gorlin syndrome features, including short stature, microtia, and absent or hypoplastic patellae, but craniosynostosis was also frequent in those patients. The severity of craniosynostosis varied widely, from unilateral or bilateral coronal synostosis to multiple suture involvement, and there was discordance for craniosynostosis in 2 brothers with the same mutation, indicating reduced penetrance for the feature. The remaining 5 patients, who had a primary presentation of craniosynostosis, exhibited mild Meier-Gorlin syndrome features, including hypoplastic ears, mild short stature, and a similar facial gestalt with small mouth. The MGORS feature of patellar hypoplasia, however, was not present in 3 of the 5 patients. Thin eyebrows were observed all 15 patients. Growth failure and microcephaly, evident from birth in almost all patients, were progressive throughout childhood. Anal abnormalities, including imperforate anus or anterior placement, were present in 7 patients from both cohorts.

By whole-genome or exome sequencing in patients with craniosynostosis, Fenwick et al. (2016) identified 2 unrelated patients with syndromic craniosynostosis who were compound heterozygous for mutations in the CDC45 gene (see, e.g., 603465.0001-603465.0004). Screening of CDC45 in a cohort of 467 patients with craniosynostosis revealed 1 more patient with biallelic mutations, and interrogation of exome-sequencing data from 52 patients with primordial dwarfism identified a patient with mutations in CDC45 who had been diagnosed with Meier-Gorlin syndrome. Sequencing of CDC45 in 34 patients with MGORS, who were negative for mutation in known MGORS-associated genes, identified 9 patients from 7 families who were homozygous or compound heterozygous for CDC45 mutations (see, e.g., 603465.0005-603465.0007). In addition, exome sequencing in 2 fetuses from a Dutch family with syndromic craniosynostosis identified a missense variant in CDC45 (A298V; 603465.0008); analysis with MLPA probes revealed deletion of exon 5 of CDC45 on the other allele (603465.0009). The mutations segregated fully with disease in all families for which parental and sib DNA was available for testing.