Both underweight and obesity have been associated with increased mortality1,2. Underweight, defined as body mass index (BMI) ≤ 18,5 kg/m2 in adults 3 and ≤ −2 standard deviations (SD) in children4,5, is the main sign of a series of heterogeneous clinical conditions such as failure to thrive (FTT) 6–8, feeding and eating disorder and/or anorexia nervosa9,10. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported 11, 12. We previously demonstrated that hemizygosity of a ~600 kb region on the short arm of chromosome 16 (chr16:29.5–30.1Mb), causes a highly-penetrant form of obesity often associated with hyperphagia and intellectual disabilities13. Here we show that the corresponding reciprocal duplication is associated with underweight. We identified 138 (132 novel cases) duplication carriers (108 unrelated carriers) from over 95,000 individuals clinically-referred for developmental or intellectual disabilities (DD/ID), psychiatric disorders or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight (mean Z-score −0.6; p=4.4×10−4) and BMI (mean Z-score −0.5; p=2.0×10−3). In particular, half of the boys younger than 5 years are underweight with a probable diagnosis of FTT, while adult duplication carriers have an 8.7-fold (p=5.9×10−11; CI_95=[4.5–16.6]) increased risk of being clinically underweight. We observe a significant trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive feeding behaviours and a significant reduction in head circumference (mean Z-score −0.9; p=7.8×10−6). Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus, correlating with changes in transcript levels for genes mapping within the duplication but not within flanking regions. The reciprocal impact of these 16p11.2 copy number variants suggests that severe obesity and being underweight can have mirror etiologies, possibly through contrasting effects on eating behaviour.

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.

Mutations of the X-linked gene PTCHD1 are associated with autism spectrum disorders and intellectual disability.

No abstract

The common constellation of features found in the two affected subjects indicates that they have a newly recognised microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 4.5-Mb segment of the 2p15-16.1 region.

This preliminary study shows that array-CGH is useful for detecting CNVs in cases of RPL. Further investigations of CNVs, particularly those involving genes that are imprinted in placenta, in women with RPL could be worthwhile.

Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.

IntroductionFanconi anemia (FA) is an autosomal recessive disease of childhood characterized by progressive pancytopenia, various developmental abnormalities, and a predisposition to acute myeloid leukemia. 1 Most individuals with FA, however, succumb to the complications of aplastic anemia. 2 FA cells demonstrate increased sensitivity to DNA cross-linking agents such as mitomycin C (MMC), diepoxybutane, and cisplatin, 2,3 a feature that serves as the basis for an important diagnostic test. FA cells treated with these cross-linking agents show a striking increase in double-strand DNA breaks and inhibited growth with cell cycle arrest in G 2 . 2 To date at least 7 potential FA genes have been indicated by complementation studies, and most of these genes, FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG, whose mutations account for 6 of the complementation groups, have now been characterized. [4][5][6][7][8][9][10] Despite the variety of genes involved in this disorder, mutations in FANCA and FANCC account for approximately 80% of all patients with FA. 11 Murine Fancc, being highly similar to the human ortholog, is able to complement human cells deficient in FANCC, restoring MMC resistance. 12 Fancc-deficient mouse strains were generated through gene targeting. Both had similar phenotypes, 13,14 demonstrating compromised gametogenesis, and an increase in the number of chromosomal aberrations, both spontaneously and after exposure to MMC. However, the targeted lines recapitulated neither the developmental nor the hematologic defects typical of human FA. 13,14 The reason for this interspecies discordance is unknown, but it has limited the utility of the mutant mice as potential models of FA.A number of hypotheses regarding the nature of the primary defect in FA have been suggested, including the proposal that FA proteins constitute a DNA damage recognition and signaling pathway, whose impairment is manifested by chromosomal instability and increased sensitivity to interstrand DNA cross-linking agents. 15 Although a reduced ability to process DNA cross-links is clearly evident, it has also been proposed that an abnormal reduction of MMC in FA cells leads to the production of reactive species that in turn generate cross-links and other types of oxidative lesions. 16 Thus, FA might also result, at least in part, from an abnormal regulation of cell redox state or of the cellular response to oxidative stress or both. In support of this notion, addition of Cu/Zn superoxide dimutase (SOD) to the culture medium of FA cells was reported to attenuate chromosomal breakage as well as MMC cytotoxicity, 16 an effect also observed in FA cells overexpressing thioredoxin. 17 In keeping with an inability to regulate either production, or the consequences of reactive oxygen species (ROS), some FA cells were shown to be hypersensitive to oxygen. 16,18 Thus, cells grew slowly at elevated oxygen levels (eg, 35%) and For personal use only. on May 9, 2018. by guest www.bloodjournal.org From tended to arrest at G 2 , whereas at low oxygen conc...