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Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification., Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

To evaluate whether early childhood body mass index (BMI) is an appropriate indicator for monogenic obesity. A cohort of n = 21 children living in Germany or Austria with monogenic obesity due to congenital leptin deficiency (group LEP, n = 6), leptin receptor deficiency (group LEPR, n = 6) and primarily heterozygous MC4 receptor deficiency (group MC4R, n = 9) was analyzed. A control group (CTRL) was defined that consisted of n = 22 obese adolescents with no mutation in the above mentioned genes. Early childhood (0–5 years) BMI trajectories were compared between the groups at selected time points. The LEP and LEPR group showed a tremendous increase in BMI during the first 2 years of life with all patients displaying a BMI >27 kg/m2 (27.2–38.4 kg/m2) and %BMIP95 (percentage of the 95th percentile BMI for age and sex) >140% (144.8–198.6%) at the age of 2 years and a BMI > 33 kg/m2 (33.3–45.9 kg/m2) and %BMIP95 > 184% (184.1–212.6%) at the age of 5 years. The MC4R and CTRL groups had a later onset of obesity with significantly lower BMI values at both time points (p 27.0 kg/m2 or %BMIP95 > 140% at the age of 2 years and BMI values >33.0 kg/m2 or %BMIP95 > 184% at the age of 5 years may be useful cut points to identify children who should undergo genetic screening for monogenic obesity due to functionally relevant mutations in the leptin gene or leptin receptor gene.

Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5–20 years) and adulthood (ages 20–45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown. RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations. RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10−10). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years). CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.

Childhood obesity is a growing health concern, associated with significant physical and psychological morbidity. Childhood obesity is known to have a strong genetic component, with mutations in themelanocortin-4 receptor(MC4R) gene being the most common monogenetic cause of obesity. Over 166 differentMC4Rmutations have been identified in persons with hyperphagia, severe childhood obesity, and increased linear growth. However, it is unclear whether the MC4-R deficiency phenotype is due to haploinsufficiency or dominant-negative effects by the mutant receptor. We report the case of a four-and-a-half-year-old boy with an interstitial deletion involving the long arm of chromosome 18 (46,XY,del(18)(q21.32q22.1)) encompassing theMC4Rgene. This patient presented with tall stature and hyperphagia within his first 18 months of life leading to significant obesity. This case supports haploinsufficiency of MC4-R as it describes a MC4-R deficiency phenotype in a patient heterozygous for a fullMC4Rgene deletion. The intact functional allele with MC4-R haploinsufficiency has the potential to favor a therapeutic response to gastric surgery. Currently, small molecule MC4-R agonists are under development for pharmacologic therapy.

Obstructive sleep apnea (OSA) is a highly prevalent medical condition in obese children and is associated with significant neurocognitive, cardiovascular and metabolic derangements. Monogenic forms of obesity resulting from disruption of the leptin-melanocortin pathways have become more notable in recent years and distinguish between various obese phenotypes. However, the association of such disorders with OSA is not well established in children or adults. In this report, we describe a 23-month-old female with morbid obesity and OSA, who was found to carry a defect in the melanocortin-4 receptor (MC4R) pathway. This report emphasizes the genetic basis of obesity related to MC4R deficiency and OSA in children.

Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two-base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to alphaMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.

As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.

The neural regulation of bone remodeling has proven to be increasingly complex at the molecular level because it involves both positive and negative mediators of bone formation and resorption. One of the mediators expressed in hypothalamic neurons that leptin uses to inhibit osteoclast differentiation and thereby bone resorption is cocaine- and amphetamine-regulated transcript (CART). CART expression in the hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r−/− mice). Moreover, we show here that humans or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass, and an increase in CART serum levels and/or hypothalamic expression. To demonstrate that the Cart overexpression is the only identifiable cause for the high bone mass observed upon Mc4r inactivation, we removed one allele of Cart from mice either heterozygous or homozygous for Mc4r inactivation. This manipulation sufficed to either significantly improve or normalize bone resorption parameters, without improving the energy metabolism disturbance that characterizes Mc4r-deficient mice. These results identify CART signaling as the main if not only molecular pathway accounting for the decrease in bone resorption leading to high bone mass in mice and humans deficient in Mc4r. As importantly, they also indicate that CART regulates bone resorption independently of the role it may exert in energy metabolism, suggesting that the neural control of appetite and bone remodeling are independent of each other.