The Laboratory of Clinical Genomics (LCG) consists of two laboratories and the Unit on Pediatric Genetics and the Section on Developmental Genomics. Investigators within the LCG have initiated three new clinical studies. Under the direction of lead investigator Margarita Raygada, the first focuses on the natural history of inborn errors of metabolism and birth defects, specifically those associated with deficits in central nervous function. The second study, just initiated, is investigating gene-modifiers, specifically insulin, IGF, and related growth factors, in patients with breast cancer while the third study, also just initiated, is exploring the genetic consequences of the BSCL2 locus (chromosome 11Q13) defect in Berardinelli congenital lipodystrohy.

Stephen Kaler heads the Unit on Pediatric Genetics, which has focused on inborn errors of trace metal metabolism, specifically copper metabolism and the copper-transport disorder Menkes’ kinky hair disease. Dr. Kaler is also investigating the causes of the human platelet disorder Bernard-Soulier syndrome and the X chromosome–linked Rett syndrome and the related phenotype PHACE.

The Section on Developmental Genomics, led by Owen Rennert, has focused on identifying the network of genes expressed in germ cells at four different stages of spermatogenesis, namely, gonocyte, type A spermatogonia, pachytene spermatocyte, and round spermatid. The laboratory achieved the identification of differentially expressed genes by using cDNA microarray hybridization and mapping the transcriptome with Serial Analysis of Gene Expression (SAGE). The research team identified 240 differentially expressed genes, more than one-quarter of which were previously uncharacterized. Genes responsible for signal transduction, energy metabolism, biosynthesis, and cellular transport were preferentially expressed in spermatids while genes for chromatin remodeling were expressed only in spermatocytes. Analyses of SAGE libraries allowed identification of more than 23,300 genes, among which 699 were specific for type A spermatogonia, 3,199 were specific for pachytene spermatocytes, and 2,836 were specific for round spermatids. More than 2,500 of these genes were novel. This number of germ cell genes is far greater than that contained in any known database and constitutes a rich source of information for future studies on genetic regulation of spermatogenesis.

Members of the section have continued their investigation of the molecular genetics of the luteinizing hormone/gonadotropin receptor (LHR) in human diseases. They identified a homozygous Leu502Pro substitution in transmembrane helix (TM) IV of the LHR, which causes a severe form of Leydig cell hypoplasia. This substitution probably disrupts the a helical structure of TM IV, resulting in inactivation of LHR. It is the first disease-causing mutation identified in TM IV of LHR, suggesting that TM IV plays an important role in the active-inactive transition of the receptor.
A new project was initiated to identify genetic risk factors for the development of pseudotumor cerebri (PTC). Although the majority of cases are non-familial, reports of familial PTC have suggested the possibility of some genetic variation/defect that may become clinically apparent after exposure to a precipitating agent. Studies of a Turkish cohort of PTC patients resulted in identification of a single nucleotide substitution in exon 10 of the coagulation Factor V, which was significantly associated with the development of PTC. This is the first study to document a genetic risk factor for PTC.