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A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Santhosh Girirajan et al. Nat Genet. 2010 Mar.

Abstract

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

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Conflict of interest statement

Competing Financial Interest: Evan E. Eichler is a Pacific Biosciences SAB member. Jill A. Rosenfeld and Blake C. Ballif are employees of Signature Genomic Laboratories, LLC. Lisa G. Shaffer is an employee of, owns shares in, and sits on the Members' Board of Signature Genomic Laboratories, LLC.

Figures

Fig. 1
Fig. 1. High-resolution array-based CGH characterization of 16p12.1 microdeletion
Validation of 16p12.1 microdeletions, in a representative set of cases, using high-resolution tiling-path custom array-based CGH is shown. Probes with log2 ratios above or below a threshold of 1.5 standard deviations from the normalized mean log2 ratio are colored green (duplication) or red (deletion), respectively. Dotted lines represent breakpoint regions. SG01-13 and SGA3-SGA7 are cases with indications of developmental delay or cognitive disability, sample 43163 is from GAIN schizophrenia study, and LD1205-03 has schizophrenia and intellectual disability (from family LD1205). Note, samples 26140 and 18125 were analyzed as part of the GAIN control cohort for schizophrenia. It is noteworthy that one control (26140) was retrospectively diagnosed with a major depressive disorder. Six RefSeq genes map within the 16p12.1 microdeletion. Four cases (SG04, SG07, SG11, affected with hypoplastic left heart syndrome, and LD1205-03 diagnosed with schizophrenia) were sequenced for CDR2, EEF2K, and UQCRC2; no recessive mutations were identified.
Fig. 2
Fig. 2. Genomic structure of 16p12.1 region
(a) A schematic of the 16p12.1 region shows the location of the microdeletion flanked by directly oriented 68-kbp segmental duplication blocks (red boxes). The segmental duplication blocks (red and gray boxes) are connected by the green and blue lines to indicate direct or inverted orientation, respectively. Also shown are representative genes in the region with the transcriptional direction. CNP indicates the copy-number polymorphism annotated by SNP genotyping for this region (CNP2157). (b) FISH analysis was performed on lymphoblast cell line from GM18956 utilizing fosmid probes mapping to the 68-kbp duplicon (WIBR2-2031K01, shown in red) and the flanking unique regions (WIBR2-3632J22 in green and WIBR2-1829F15 in blue). Results show that the 68-kbp duplicon is polymorphic, i.e. it has a variable number of copies and that the orientation of the region is inverted in this HapMap sample compared to the human genome reference assembly. High copy numbers of the segmental duplications have complicated mapping of the inversion breakpoint for this region.
Fig. 3
Fig. 3. Representative photographs of individuals with 16p12.1 microdeletion
Facial features of patient SG07 at 22 months (a), patient SGA3 at 2.5 y (b), patient SGA5 at 2 y (c), patient SG04 at 15 months (d), patient SG10 at 2 y (e), and patient 25514 at 5 y (f) are shown. Specific consents were obtained to publish these patient photographs.
Fig. 4
Fig. 4. Family pedigrees of probands with 16p12.1 microdeletion
Large CNVs, outside of 16p12.1 region, in a representative set of individuals with 16p12.1 microdeletions are shown (a-d). The CNV regions are indicated by dotted lines and the cytogenetic extent and size are labeled. We utilized a 135K NimbleGen array to identify these CNVs (with average probe density of 2.5 kbp in regions flanked by segmental duplications and a genomic backbone of 35 kbp). CNV calls were made using a Hidden Markov Model CNV-calling algorithm described previously . Also shown are the pedigrees of individuals with 16p12.1 microdeletion with known available parental information (e). Circles indicate females and squares indicate males. Intellectual disability and congenital malformation category also includes congenital heart defects and seizures. Psychiatric illness includes depression or bipolar disorder, attention deficit hyperactive disorder, and abnormal behaviors. Note that there is an excess of transmitting parents with the microdeletion who also manifested with a phenotype. NT = not tested.
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