Duyvenvoorde, H.A.

Kant, S.G.

Karperien, H.B.J.

Losekoot, M.

Mul, D.

Oostdijk, W.

Pereira, A.M.

Ruivenkamp, C.A.

Wit, J.M.

English

Karperien, M.

NARCIS 

A quest for copy number variations causing extreme tall stature

University of Twente Research Information

A quest for copy number variations causing extreme tall statureH.A. van Duyvenvoorde1, C.A.L. Ruivenkamp1, D. Mul2, W. Oostdijk1, M. Karperien3, M. Losekoot1 A.M. Pereira1, S.G. Kant1, and J.M. Wit1Leiden University Medical Center, Leiden1, Haga Hospital/Juliana Children’s Hospital, Den Haag2 and University of Twente, Enschede3, the NetherlandsIntroductionHeight is a highly heritable and classic polygenic trait. Inthe majority of individuals with extreme tall stature (ETS)no genetic cause is known. We performed genome-wideanalysis for copy number variants (CNVs) in people withETS using single nucleotide polymorphism (SNP) arrays,in an effort to identify novel rare variants that mayinfluence height.ResultsIn 4 cases (3 males) potentially pathogenic CNVs were identified and further analyzed. There was no segregation in 2 cases.In a 204.2 cm (+2.9 SDS) tall male, a 1p34.1 duplication (Fig. 1) containing part of MAST2 and PIK3R3 (Fig. 2) was observed.The duplication was in tandem, i.e. one copy following the other in the same orientation (Fig. 3). In silico analysis showed thatPIK3R3 binds the intracellular part of the IGF1R. The duplication segregated with tall stature (+1.9 and +1.8 SDS). A similarduplication was identified in our in-house reference set, but without tall stature. PIK3R3 sequencing in 152 tall and 80 shortstature patients identified an intronic duplication (c.764+2dup) in 4 patients with tall stature. However, the same duplicationwas also present in an in-house exome dataset suggesting that it is a rare polymorphism.In a male with a height of 201.9 cm (+2.5 SDS) 3 aberrations were detected; a duplication of 12q21.1 not segregating with tallstature, a 13q33.1 deletion without any genes and an extra copy of the Y chromosome (47,XYY).ConclusionWhole genome SNP array and segregation analysisidentified potentially pathogenic CNVs in 2 cases (11%).The 1p34.1 duplication, although of interest because itcontains part of PIK3R3, is probably not the cause ofETS. The extra Y chromosome in the other case isknown to contribute to increased height, but the role ofthe 13q33.1 deletion still remains unclear.H.A.van_Duyvenvoorde@lumc.nlSubjects and MethodsClinical and family history of 18 adults with ETS wereobtained and whole genome SNP array (Affymetrix 262KNspI arrays) analysis was performed. All potentiallypathogenic CNVs were assessed with Ensembl andDECIPHER for gene content and similar cases.If possible, segregation analysis was performed.HvD received grant support from Novo Nordisk (The Netherlands) Clinical resultsHeight Head Circumferencecm SDS cm SDSMen (11) 201.9 – 212.4 +2.5 – +4.0 55.7 – 62.0 -1.2 – +2.4Women (7) 185.9 – 198.9 +2.4 – +4.4 54.5 – 58.8 -0.5 – +2.1Table 1. Height and head circumference range (in cm and SDS) of the 18 adults with ETS.Wildtype 200M7 dig 533D7 bio533D7 bio200M7 digDirect duplicationFig. 3. Fiber FISH to identify the location and orientation of the 1p34.1 duplication.Fig. 1. Affymetrix SNP array results.Fig. 2. Ensembl output of the duplicated area, containing part of MAST2 and PIK3R3.

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A quest for copy number variations causing extreme tall stature

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