Fifty microdeletions among 112 cases of Sotos syndrome: Low copy repeats possibly mediate the common deletion

Abstract

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

“…The duplication on Case 1 was confirmed using real-time quantitative PCR (RT-qPCR), as previously described, 19 with a probe within CTB-87L24 (Figure 1b) in the duplicated region. The parents' DNA was also investigated using RT-qPCR.…”

“…[15][16][17] The portion of the human genome surrounding NSD1, often referred to as the Sotos critical region, encompasses 1.1 Mb of DNA, contains approximately 21 genes ( Figure 1a) and is flanked by two well-characterized low-copy repeats ( Figure 1c): a proximal 390 kb repeat (Sos-PREP) and a distal 429 kb repeat (Sos-DREP). 18 A common microdeletion 19 mediated by directly oriented subunits within Sos-PREP and Sos-DREP 18 is the most common mutational mechanism in the Japanese population, whereas intragenic mutations are responsible for at least 80% of the reported cases in European and North American patients.…”

Identification and characterization of cryptic SHOX intragenic deletions in three Japanese patients with Léri–Weill dyschondrosteosis

“…Although the cause of the difference in the frequency of SHOX abnormalities (especially deletions) remains to be examined, this could be due to ethnic differences. Indeed, deletions encompassing NSD1 for Sotos syndrome are also much more frequently identified in Japanese than in other ethnic groups (Kurotaki et al 2003).…”

The DNA sequence and comparative analysis of human chromosome 5

“…So far, mutations in 66 specific genes are known for mendelian diseases (see Supplementary Table S5) 30 . In addition to SMA, microdeletions in a duplicated region in 5q35 cause Sotos syndrome, a debilitating disorder that results in cranial overgrowth and mental retardation 31 , in which the duplication is thought to mediate severity 32 . The availability of this completed sequence will further advance our understanding of human disease, and the rate at which disease genes are identified and cloned with causative mutations should be greatly accelerated.…”