Stefanie B. Uhrich

Recommendations for standardized human pedigree nomenclature

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to >100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

Genetic counseling and screening of consanguineous couples and their offspring: Recommendations of the national society of genetic counselors

The objective of this document is to provide recommendations for genetic counseling and screening for consanguineous couples (related as second cousins or closer) and their offspring with the goals of1. providing preconception reproductive options2. improving pregnancy outcome and identifying reproductive choices3. reducing morbidity and mortality in the 1st years of life, and4. respecting psychosocial and multicultural issues.The recommendations are the opinions of a multicenter working group (the Consanguinity Working Group (CWG)) with expertise in genetic counseling, medical genetics, biochemical genetics, genetic epidemiology, pediatrics, perinatology, and public health genetics, which was convened by the National Society of Genetic Counselors (NSGC). The consensus of the CWG and NSGC reviewers is that beyond a thorough medical family history with follow-up of significant findings, no additional preconception screening is recommended for consanguineous couples. Consanguineous couples should be offered similar genetic screening as suggested for any couple of their ethnic group. During pregnancy, consanguineous couples should be offered maternal–fetal serum marker screening and high-resolution fetal ultrasonography. Newborns should be screened for impaired hearing and detection of treatable inborn errors of metabolism. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

Genetic Evaluation and Counseling of Couples with Recurrent Miscarriage: Recommendations of the National Society of Genetic Counselors

The objective of this document is to provide recommendations for genetic evaluation and counseling of couples with recurrent miscarriage (RM). The recommendations are the opinions of the multidisciplinary Inherited Pregnancy Loss Working Group (IPLWG), with expertise in genetic counseling, medical genetics, maternal fetal medicine, internal medicine, infectious disease, cytogenetics, and coagulation disorders. The IPLWG defines RM as three or more clinically recognized consecutive or non-consecutive pregnancy losses occurring prior to fetal viability (<24 weeks gestation). These recommendations are provided to assist genetic counselors and other health care providers in clinical decision-making, as well as to promote consistency of patient care, guide the allocation of medical resources, and increase awareness of the psychosocial and cultural issues experienced by couples with RM. The IPLWG was convened with support from the March of Dimes Western Washington State Chapter and the University of Washington Division of Medical Genetics. The recommendations are U.S. Preventive Task Force Class III, and are based on clinical experiences, review of pertinent English-language published articles, and reports of expert committees. This document reviews the suspected causes of RM, provides indications for genetic evaluation and testing, addresses psychosocial and cultural considerations, and provides professional and patient resources. These recommendations should not be construed as dictating an exclusive course of medical management, nor does the use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the circumstances of a specific case, should always supersede these recommendations.

Isolated fetal choroid plexus cysts and karyotype analysis: is it necessary?

The purpose of this study was to evaluate the risk of fetal aneuploidy in the presence of isolated choroid plexus cysts and to evaluate the results obtained from our institution and those reported previously in the English literature. All patients with fetal choroid plexus cysts on prenatal ultrasonography were offered genetic counseling and amniocentesis for fetal karyotyping. Seven of 274 fetuses, 2.6% (95% confidence interval = 1.0 to 5.2%), with isolated choroid plexus cysts were aneuploid. Literature analysis located 23 other reports of 1537 fetuses with isolated choroid plexus cysts; 26 were karyotypically abnormal, 1.7% (95% confidence interval = 1.0 to 2.4%). When evaluating only those patients whose indication for amniocentesis was choroid plexus cysts (i.e., eliminating those patients with advanced maternal age or abnormal serum screening) the risk of having a fetus with trisomy 18 changed little, 1.9% (95% confidence interval = 0.4 to 5.5%). Our data, combined with those of the literature, suggest that the risk of finding an abnormal fetal karyotype in the presence of isolated choroid plexus cysts is at least 1% and may be as high as 2.4%. On the basis of these results, genetic counseling and prenatal diagnosis should be offered to these patients.

Second-trimester biparietal diameter/nasal bone length ratio is an independent predictor of trisomy 21.

The purpose of this study was to evaluate the association between the second‐trimester fetal biparietal diameter/nasal bone length (BPD/NBL) ratio and trisomy 21.

Four Mutations in the SI Gene Are Responsible for the Majority of Clinical Symptoms of CSID

1. Prader A, Auricchio S, Muerset G. D rchfall infolge hereditaren Mangels an intestinaler Saccharaseaktivitat (Saccharoseintoleranz). Schweizerischen Mediz Wochenschr 1961;91:465–75. 2. Robayo-Torres CC, Opekun AR, Quezada-Calvillo R, et al. 13C-breath tests for sucrose digestion in congenital sucrase isomaltase-deficient and sacrosidase-supplemented patients. J Pediatr Gastroenterol Nutr 2009; 48:412–8. 3. Auricchio S, Ciccimarra F, Moauro L, et al. Intraluminal and mucosal starch digestion in congenital deficiency of intestinal sucrase and isomaltase activities. Pediatr Res 1972;6:832–9. 4. Dahlqvist A. Assay of intestinal disaccharidases. Anal Biochem 1968; 22:99–107. 5. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. In: Drossman DA, Corazziari E, Talley NJ, et al, eds. Rome II: The Functional Gastrointestinal Disorders. 2nd ed. McLean, VA: Degnon Associates; 2000: 302. 6. Karnsakul W, Luginbuehl U, Hahn D, et al. Disaccharidase activities in dyspeptic children: biochemical and molecular investigations of maltaseglucoamylase activity. J Pediatr Gastroenterol Nutr 2002;35:551–6. 7. Dahlqvist A, Auricchio S, Semenza G, et al. Human intestinal disaccharidases and hereditary disaccharide intolerance. The hydrolysis of sucrose, isomaltose, palatinose (isomaltulose), and a 1,6-alpha-oligosaccharide (isomalto-oligosaccharide) preparation. J Clin Invest 1963;42:556–62. 8. Leeds JS, Hopper AD, Sidhu R, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol 2010;8:433–8.

The need for developing standardized family pedigree nomenclature.

To assess the variation in usage of symbols used in recording a genetic family history, full members of the National Society of Genetic Counselors were surveyed by questionnaire. The questionnaire return rate was 55.3% and genetic counselors from a broad range of clinical experience, genetic counseling training programs and geographic regions responded. There was striking variation in symbols used for recording routine medical information in a genetic family history (i.e., pregnancy, spontaneous abortion, termination of pregnancy). There was even less consensus in recording situations representing new reproductive technologies (i.e., artificial insemination by donor semen, donor ovum, surrogate motherhood). The results of this survey document the need for developing standardized nomenclature in recording genetic family histories as a quality assurance measure in the delivery of genetic services. Such standardization will reduce the chance of incorrect interpretation of patient and family medical and genetic information.

Amniotic fluid alpha-fetoprotein determination at the time of genetic amniocentesis : Has it outlived its usefulness ?

The purpose of this retrospective study was to evaluate the utility of routine measurement of amniotic fluid alpha‐fetoprotein levels at the time of second trimester genetic amniocentesis (mean gestational age, 17.3 weeks +/‐ 2.5 weeks standard deviation; median, 16.8 weeks; range, 15 to 22 weeks). During the study period 7174 patients underwent second trimester genetic amniocentesis. Outcome data were available in all cases. In 79 (1.1%) cases the amniotic fluid alpha‐fetoprotein level was > or = 2.0 multiples of the median. Thirty‐three of the 79 (42%) patients had normal ultrasonograms, and in 31 of 33 (94%) the amniotic fluid alpha‐fetoprotein level was between 2.0 and 3.0 multiples of the median. Forty‐six of the 79 (58%) patients had abnormal ultrasonographic findings, and of these, 82% were neural tube defects, abdominal wall defects, or cystic hygromas. Acetylcholinesterase was positive in 37 cases, all of which had abnormal ultrasonographic findings. None of the fetuses with negative findings on sonographic screening had detectable abnormalities at birth. In this study, with over 7000 patients, amniotic fluid alpha‐fetoprotein and acetylcholinesterase levels did not increase the detection of fetal abnormalities. On the basis of these results, routine measurement of amniotic fluid alpha‐fetoprotein level at the time of routine genetic amniocentesis (15 to 22 weeks) does not appear justified.

Detecting the effects of Fabry disease in the adult human brain with diffusion tensor imaging and fast bound‐pool fraction imaging

To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound‐pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder.

Research progress reported at the 50th Anniversary of the Discovery of Congenital Sucrase-Isomaltase Deficiency Workshop.

C ongenital sucrase-isomaltase deficiency (CSID) is a rare autosomal intestinal disease caused by mutations of the sucrase-isomaltase gene. Patients with CSID have different phenotypes and enzymatic activities associated with sucrase-isomaltase ranging from mild reduction of sucrase activity to complete absence. Low sucrase activity leads to maldigestion of sucrose, resulting in dyspepsia-like symptoms such as chronic diarrhea, abdominal pain, and bloating. The severity of the symptom is related to the amount of sucrase activity and quantity of sucrose ingested. Reduced maltase activity is expected to occur in patients with CSID because both subunits of the SI complex contribute to the total mucosal maltose activity. Indeed, low maltase activity can also lead to maldigestion of starches contributing to the symptoms of dyspepsia. When children are assessed for this gene mutation, duodenal mucosal histology is invariably normal. Because there are no noninvasive methods for specific confirmation of sucrase-isomaltase deficiency, a novel noninvasive C-sucrose labeled substrate has been developed and validated as a sucrase activity breath test for screening and confirmation of CSID. It has been shown that primary sucrase deficiency can be confirmed using this new C breath test, as well as the effectiveness of sucrase replacement therapy. On December 21 and 22, 2011, the 8th Workshop of the Starch Digestion Consortium (SDC) was held at the Children’s Nutrition Research Center at the Baylor College of Medicine and Texas Children’s Hospital. The theme of the workshop was ‘‘50 Years of Progress Since Congenital Sucrase-Isomaltase Deficiency (CSID) Recognition.’’ This was a multidisciplinary workshop that blended clinical medicine with nutritional and food science. The purpose of this workshop was to review progress toward clinical diagnosis and management of sucrase-isomaltase enzyme deficiency during the past 50 years. The nutritional and food technological objectives of the conference were 2-fold: first, to define the role of sucrase-isomaltase enzyme complex in human starch digestion to glucose (a-glucogenesis), and second, by studying sucrase-isomaltase–deficient patients with CSID, envision approaches to botanical and technological alterations in food that will benefit all populations. More than 50 authors and attendees participated in this workshop from 12 different countries. Eighteen original communications were presented. Special thanks go to QOL Medical, the supplier of Sucraid oral enzyme supplement, for sponsoring this event. This supplement to the Journal of Pediatric Gastroenterology and Nutrition reports the proceedings of this workshop. E. Roseland Klein served as the technical editor of the workshop publication. Beth Mays was responsible for all travel arrangements and the workshop organization. Adam Gillum was responsible for graphic and audio arrangements. The group of participants standing among the lobby statuary at the SDC/CSID workshop held at the Children’s Nutrition Research Center, December 21–22, 2011 is shown in Figure 1. Statues are identified by italics; Borden is by Joseph Paderewski (1914–2000) and the others are copies of the work of Elizabet Ney (1833–1907). Research Progress Reported at the 50th Anniversary of the Discovery of Congenital Sucrase-Isomaltase Deficiency Workshop