Chromosome 1p36 Deletions: The Clinical Phenotype and Molecular Characterization of a Common Newly Delineated Syndrome

Abstract

Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap.

FISHing for mechanisms of cytogenetically defined terminal deletions using chromosome-specific subtelomeric probes

“…This allowed for the classification of these cases into groups based on the structure at the end of the deleted chromosome 1 (Table 1). Prior to the subtelomeric FISH, six patients were known to have rearranged chromosomes and were included as controls: one case had a satellited 1p, one case was the unbalanced segregant from a t (1;22)pat, 26 one case was previously determined to have 1q sequences on distal 1p based on the G-banding pattern and confirmed by a chromosome 1 paint, and three patients had known interstitial deletions, based on molecular studies. 24 The subtelomeric FISH identified five patients carrying de novo rearrangements indicative of telomere capture (Figure 1).…”

“…31,32 One, newly recognized, deletion syndrome is monosomy 1p36. 24,26,33 This deletion syndrome is quite common in the population, with an estimated incidence of 1 in 10 000 newborns. 26 Herein, we investigated 33 patients with cytogenetically defined terminal deletions of 1p36 and found interstitial deletions, and evidence for telomere healing and telomere capture mechanisms.…”

“…Table 2 contains a list of all reported derivative chromosomes involving 1p36 that resulted in deletion. 24,26,[34][35][36][37][38][39][40][41][42][43][44] Translocation events involving 1p have been reported to occur with a wide variety of chromosome ends. Some cytogenetic rearrangements have been reported more than others and a better understanding of these particular rearrangements could provide insights into the formation and stabilization of cytogenetically defined terminal deletions of chromosome 1p through telomere capture.…”

Detection of submicroscopic aberrations in patients with unexplained mental retardation by fluorescence in situ hybridization using multiple subtelomeric probes

“…4 -14 Efforts have been made to establish strategies for screening cryptic subtelomeric rearrangements, because this type of aberration is considered to be an important cause of unexplained mental retardation. 6,8,15 A FISH strategy using multiple subtelomeric probes has been developed recently. 16 However, by using the new FISH technique, the detection rates have ranged from Ͻ1% to as high as 23% of the patients studied.…”

“…These features are consistent in general with the phenotype described for patients with a 1p36 deletion. 8 …”