The Growing Complexity of the Monosomy 1p36 Syndrome

Abstract

Even before the first draft of the human reference genome and the genome-wide screening methods based on this reference became available, several recognizable ‘deletion syndromes’ were known to the medical genetics community. For instance, a syndrome characterized by distinct dysmorphic features, such as large anterior fontanels, microcephaly, brachycephaly, deep-set eyes, flat nose and nasal bridge, and a pointed chin was found in ∼1 out of 5,000 live births [Shapira et al., 1997; Slavotinek et al., 1999; Gajecka et al., 2007]. By classical karyotyping and FISH, a deletion in the 1p36 region of one of the chromosomes of the patient was detected. Thus, ‘deletion 1p36’ or ‘monosomy 1p36’ became the most common terminal deletion syndrome in humans. Patients with monosomy 1p36 often show hypotonia, brachycamptodactyly, short feet, intellectual disability, and speech problems. Less frequently, congenital heart defects, vision problems, including visual inattention, seizures, sensorineural deafness, gastrointestinal anomalies, hypothyroidism, and anomalies of the kidneys and the external genitalia are also observed [Battaglia, 1993]. Genome-wide aneuploidy screening with BAC-, oligonucleotide and SNP arrays revealed a remarkable variability in size and position of the terminal and interstitial deletions in these patients. These findings have been used to map and identify candidate genes for some of the clinical features of monosomy 1p36 patients [Jordan et al., 2015]. More detailed molecular cytogenetic studies with higher resolution arrays revealed an unexpected complexity of 1p36 rearrangements and gave rise to speculations as to its putative mechanism(s) of origin [Ballif et al., 2003; Zanardo et al., 2014; Gamba et al., 2015].