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The clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha- galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals' beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

There is essentially unanimous agreement that newborn screening saves lives. Nevertheless, newborn screening—rated as one of the top 10 successes in public health in the first decade of the twenty-first century by the Centers for Disease Control and Prevention (Koppaka in JAMA 306(5):484–487, 2003)—faces multiple challenges, including questions about how conditions are added to the list of disorders for which screening is done in each state, about the need for parental consent for use of dried blood spots after screening, and the roles of parents in expansion of newborn screening. Such questions figure prominently in controversy surrounding Pennsylvania’s recent passage of House Bill1654, also called Hannah’s Law, which institutes newborn screening and follow-up for 6 lysosomal storage disorders including Krabbe, Fabry, Pompe, Niemann–Pick, types A and B, Gaucher diseases, and mucopolysaccharidosis type I, also called Hurler disease. This review article provides an historical perspective on newborn screening including discussion of how conditions came to be added to the Recommended Uniform Screening Panel, and an overview of current issues and concerns for key stakeholders including parents, healthcare providers, laboratorians, and legislators.

An important part of the coordinated care by experienced health care teams for all Pompe disease patients, whether diagnosed through newborn screening (NBS), clinical diagnosis, or prenatal diagnosis, is genetic counseling. Genetic counseling helps families better understand medical recommendations and options presented by the patient’s health care team so they can make informed decisions. In addition to providing important information about the inheritance and genetic risks, genetic counseling also provides information about Pompe disease and available treatments and resources and should be offered to families with an affected child and all adults diagnosed with Pompe disease. Although the need for genetic counseling after a positive newborn screen for Pompe disease is recognized, the role that genetic counseling plays for both families of affected patients and health care teams is not fully understood. Consistent best genetic counseling practices also are lacking. The guidance in this article in the “Newborn Screening, Diagnosis, and Treatment for Pompe Disease” supplement is derived from expert consensus from the Pompe Disease Newborn Screening Working Group. It is intended to help guide genetic counseling efforts and provide a clear understanding of the role for families or carriers of Pompe disease identified through NBS; explain special considerations (eg, diagnosis of late-onset Pompe disease before the appearance of symptoms) and the impact and implications associated with a diagnosis (eg, determination of genetic risk and carrier status and preconception counseling); and provide health care teams caring for patients with a framework for a standardized approach to genetic counseling for patients and at-risk family members.

Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients.

Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood. A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age. The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age. This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated. Genet Med 17 5, 323–330.

To the Editor: We read with interest and much concern the recent recommendation of the College regarding carrier screening in individuals of Ashkenazi Jewish (AJ) descent (Genet Med 2008;10: 54 –56). Specifically, we felt that Recommendation 4, “if only one member of a couple is of AJ background, testing should still be offered,” is quite problematic. As stated in the Guidelines, the cumulative probability of being a carrier for one of the conditions in the panel is between 20 and 25%. One in 4 or 1 in 5 couples where only one member is of AJ descent will be identified as at increased risk to have an affected child and offered testing for that specific condition for the non-AJ partner. The screening of the non-AJ partner for the mutations that occur in the AJ population is an exercise in unknown probabilities (Table 1). Since the frequency of those mutations that occur more often in the AJ population is unknown in non-AJ populations, there is no way to revise a couple’s risk after screening the non-AJ member for the AJ mutations. Counseling a couple that the non-AJ member does not carry any of the AJ mutations does not provide much solace (or information) regarding their risk for a child with one of the AJ genetic conditions. In the case of cystic fibrosis (where gene frequencies are known in various populations) and in the case of Tay-Sachs disease (where enzyme analysis is informative regardless of ethnicity) the Practice Guidelines do provide useful information that would aid a family in their decision-making process. Even without testing the non-AJ member, counselors can be reassuring to those couples where the AJ member is a carrier for Dysautonomia, Bloom syndrome, or Mucolipidosis IV, as these conditions are either extremely rare or unreported in non-AJ populations. So the question remaining (with the exception of cystic fibrosis and Tay-Sachs screening) is what do we accomplish by the implementation of these Guidelines in couples where only one member is of AJ descent? Michael L. Begleiter, MS, CGC Janda L. Buchholz, MS, CGC Andrea M. Atherton, MS, CGC Lee Z. Mays, MS, CGC Molly M. Lund, MS, CGC Meghan E. Strenk, MS Genetics, Dysmorphology and Metabolism, The Children’s Mercy Hospitals & Clinics, Kansas City, Missouri, The University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri