Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

SAM syndrome is characterized by extensive phenotypic heterogeneity.

Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life-threatening inherited condition caused by bi-allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome-causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits.

Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation.

Ghrelin and growth hormone secretagogue receptor (GHSR) genes are not commonly involved in growth or weight abnormalities in an Israeli pediatric population.

CONTEXT AND OBJECTIVE: Ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), have key roles in appetite control and growth regulation. To date, only few mutations of GHSR have been identified in children with obesity and short stature. We hypothesized that mutations in ghrelin or GHSR will result in disrupted growth and weight regulation in children. DESIGN: A total of 98 subjects (38 females and 60 males) were enrolled with failure to thrive (FIT) (n=9), GH deficiency (GHD) (n=44), idiopathic short stature (ISS) (n=22) or obesity (n=23). The coding exons of both ghrelin and GHSR genes were screened for mutations by sequencing. RESULTS: Seven different sequence changes were identified in GHSR, two of them novel and five described previously. One previously described sequence change (p.L72M) in the ghrelin gene was identified in five patients; however, the same variant was identified at a higher rate in controls. A high rate of sequence changes was shown in ghrelin and its receptor, GHSR, in our population, but none of these changes affected the coding region of the protein. CONCLUSIONS: Despite the major role of ghrelin in growth and appetite regulation, our results indicate that mutations in ghrelin and GHSR do not explain short stature and weight regulation disorders in children in our population.

High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel.

Most autosomal recessive diseases are rare in the general population, but in genetically isolated communities specific condition might be frequent, mainly due to founder effect. Recognition of common inherited disorders in defined populations may be effective in improving public health care. Cockayne syndrome (CS) is a rare autosomal recessive disorder common in Christian Arabs due to a p.Tyr322X mutation. Genetic screening of the p.Tyr322X mutation of the ERCC8 gene in this population documented a carrier frequency of 6.79% (95% confidence interval: 3.84-9.74%). The haplotype analysis data, as well as the high carriers frequency of CS, suggested that the Israeli Arab Christian CS mutation (p.Tyr322X) is an ancient founder mutation that may have originated in the Christian Lebanese community. As a result of this pilot study the Christian CS mutation was included in the genetic screening program offered to the Israeli Arab Christian community.