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.
Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3͞4 finger and 4͞5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P ؍ 0.012) and feet (P < 0.00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.Dominantly inherited disorders frequently display incomplete penetrance (a normal phenotype in some mutation carriers) and variable expressivity (different degrees of phenotypic severity in affected individuals), the molecular basis for which is generally not understood. One such disorder is the rare dominantly inherited congenital limb malformation, synpolydactyly (SPD; OMIM No. 186000). Mutations in the first exon of HOXD13 have recently been found in three American SPD families (1), expanding a 15-residue polyalanine tract encoded by an imperfect trinucleotide repeat sequence by 7, 8, and 10 additional residues, respectively. Similar 9-residue expansions subsequently have been reported in two Turkish SPD families (2). SPD typically consists of 3͞4 finger and 4͞5 toe syndactyly, with a duplicated digit in the syndactylous web (3). Incomplete penetrance and variable expressivity both between and within affected families are common (4-6). From one to four limbs can be involved, and the severity of involvement ranges from partial skin syndactyly to complete reduplication of a digit, extending as far proximally as the metacarpals͞tarsals. Associated distal limb abnormalities include fifth-finger clinodactyly, camptodactyly, or brachydactyly; variable syndactyly of the second to fifth toes; and middle phalanx hypoplasia͞ aplasia.To investigate the molecular basis for this incomplete penetrance and variable expressivity, we analyzed the genotype and phenotype of 16 new SPD pedigrees, including one with an expansion that almost doub...
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