Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions

Abstract

Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.

Mini-Review Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes

“…Deletions ranging from 199 kb to 16 Mb have been previously reported (Rosenfeld et al, 2010;Nicoulaz et al, 2011). Patients bearing 1p36 deletions of different sizes have been shown to express similar phenotypes.…”

“…Among these, 17 scientific articles met the criteria for inclusion and were selected for this study (D'Angelo et al, 2006;Krepischi-Santos et al, 2006;Kang et al, 2007;Robinson et al, 2008;Bursztejn et al, 2009;El-Hattab et al, 2010;Gajecka et al, 2010;Rosenfeld et al, 2010;Haimi et al, 2011;Mikhail et al, 2011;Nicoulaz et al, 2011;Giannikou et al, 2012;Gervasini et al, 2013;Shiba et al, 2013;Zhu et al, 2013;Shimada et al, 2014;Stagi et al, 2014). Among these, 12 were case reports and five reported series of cases.…”

“…For example, Õiglane-Shlik et al (2014) reported that only one of four patients with the same deletion on 1p36 presented congenital heart defect, seizures, and behavioral changes. On the other hand, Rosenfeld et al (2010) reported a deletion in the GABRD gene, which encodes the delta subunit of the gamma-amino butyric acid (GABA) A receptors, in three 1p36 deletion patients. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA A .…”

“…These abnormalities are commonly found in monosomy 1p36. Deletions in the SKI (Rosenfeld et al, 2010) or PRDM16 genes can lead to cardiomegaly, which is the most common abnormality found in patients according to the literature (Slavotinek et al, 1999). However, only one of the patients included in this review presented a deleted SKI gene and cardiomegaly.…”

Current Genetic Testing Tools in Neonatal Medicine

“…28 This can occur as a result of either deletion of 15q11.2 on the paternal allele or maternal uniparental disomy of chromosome 15. While several other microdeletion syndromes are clinically recognizable in the neonatal period, such as 1p36 microdeletion syndrome (dysmorphic features, hypotonia, feeding difficulties, total or partial absence of the corpus callosum, seizures, septal defects, left ventricular noncompaction), 29,30 MillereDieker syndrome (lissencephaly, seizures, atrial septal defect), and Alagille syndrome (JAG1 deletion on 20p12; characteristic facies, cholestasis, peripheral pulmonic stenosis), many genomic disorders are ascertained after the 1 st month of life, particularly those associated with neurocognitive delays, such as WilliamseBeuren syndrome (7q11.23 deletion; supravalvular aortic stenosis, failure to thrive, hypercalcemia) and SmitheMagenis syndrome (17p11.2 deletion; behavior disorder, sleep disturbance, craniofacial, septal defects). Undoubtedly, CMA undertaken for evaluation of dysmorphic features and congenital anomalies in the newborn period often uncovers these relevant genetic disorders that require prolonged multidisciplinary care.…”