John Atlas Phillips

Over the past decade, there has been increasing recognition that genetic factors play important roles in both sporadic and familial cases of idiopathic pulmonary fibrosis (IPF). Current data indicate that at least 1/3 of the risk to develop sporadic or familial IPF can be explained by common genetic variants identified through large genome-wide association studies. Interestingly, several of these loci appear to have prognostic implications for patients with IPF. In addition to common variants, a growing number of genes carrying rare genetic variants are being identified that influence susceptibility to disease in familial interstitial pneumonia (FIP), the familial form of IPF. As of yet, there is no guidance for clinicians regarding when to pursue genetic testing in IPF patients or how to utilize test results in patient care. Below, we offer our perspective on the current utility of genetic evaluation and testing in familial and sporadic IPF, as well as individuals at risk for development of IPF. Continued research investigating the genetic underpinnings of IPF is needed to support future development and validation of more comprehensive, evidence-based guidelines for genetic testing and screening for IPF.

Studies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression.

Background Small intestinal ulcers are frequent complications of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine. Methods Eicosanoids and metabolites were measured by isotope dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR. Results We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B₂ (TxB₂) production was 4.6% of normal controls (P < 0.006), and serum 12-HETE was 1.3% of controls (P < 0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB₄ biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE₄ was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A₂-α (cPLA₂-α), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA₂-α cDNA demonstrated two heterozygous nonsynonymous single-base-pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known single nucleotide polymorphism (SNP), Lys651Arg (K651R). Conclusions Characterization of this cPLA₂-α deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers.

While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Furthermore, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself.

Recent advances in newborn screening and molecular genetics are transforming our understanding of the genetic basis of diseases that affect individuals of all ages. It is essential for clinicians to understand the methods and goals of newborn screening (NBS), the principles of genetics, and the methods of molecular analysis including Southern blots, PCR amplification, DNA sequence analysis, Reverse Transcriptase PCR, Multiplex Ligation- dependent Probe Amplification analysis, Fluorescence in Situ Hybridization, Comparative Genomic Hybridization, as well as Fetal Ultrasonography. This understanding and applications of these tools can lead to genetic diagnoses by identifying risks from newborn screening results or family histories, selecting appropriate tests and understanding the implications of test results to the patient and their families. To facilitate this understanding we will review newborn screening, basic genetics, inheritance and examples of established and new methods used in genetic testing. It is our hope that this material will facilitate clinician's abilities to consider and detect genetic disorders so that earlier interventions and optimal outcomes can occur.

Human Growth Hormone gene ( GH1 ) resides on chromosome 17q22-24 and it is expressed in somatotropic cells of the anterior pituitary gland. While there are multiple causes of GH Deficiency (GHD) a significant proportion have a genetic basis. The most severe Mendelian form of IGHD, called IGHD IA, has an autosomal recessive mode of inheritance. While affected individuals can have short lengths at birth and hypoglycemia in infancy, all develop severe dwarfism by six months of age. Although short stature, delayed growth velocity, and delayed skeletal maturation all occur with IGHD, none are specific for IGHD 1A. GH1 gene deletions, frameshifts, or nonsense mutations cause complete absence of GH in IGHD 1A. Thus IGHD 1A is best described as being complete GHD caused by severe loss of function GH1 gene mutations rather than being limited to only those having GH1 gene deletions. Interestingly, GH1 gene deletions are recurring mutations that can arise through unequal recombination in meiosis rather than by allele sharing through common descent. Individuals with IGHD 1A develop severe dwarfism in early infancy and often develop anti-GH antibodies after receiving exogenous GH. These antibodies can prevent the growth response expected from exogenous GH therapy. Individuals who are heterozygous for a GH1 gene deletion but whose other GH1 allele is not deleted and produces a non truncated product are usually immune tolerant.

Genetic disorders of growth are numerous and include defects of the central nervous system, hypothalamus, pituitary, thyroid, skeleton and other glands, tissues or organs. These disorders are caused by genetic variations that interrupt different points of the hypothalamic-pituitary axis and other synthetic pathways that are required for growth. The resulting growth disorders can be classified by their 1) etiology (Mendelian, mode of inheritance or chromosomal basis), 2) phenotype (isolated or multiple hormone deficiencies), 3) genetic variations of different loci or alleles involved, and/or 4) the associated biochemical findings. The growth disorders selected for inclusion here are examples and are by no means a comprehensive list of all known genetic diseases that have some effect on growth. Information on each disorder is summarized and, for most, more detailed information can be obtained through the electronic database Online Mendelian Inheritance in Man (OMIM) which is available at http://www.ncbi.nlm.nih.gov/Omim.