Christina Alamillo

Nearly a third of abnormalities found after first‐trimester screening are different than expected:10‐year experience from a single center

This study aimed to assess the efficacy of first‐trimester aneuploidy screening in a single clinical setting.

Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies

Exome sequencing is a successful option for diagnosing individuals with previously uncharacterized genetic conditions, however little has been reported regarding its utility in a prenatal setting. The goal of this study is to describe the results from a cohort of fetuses for which exome sequencing was performed.

Genetic assessment following increased nuchal translucency and normal karyotype

The objective of this study was to assess the first formal approach for monitoring genetic/developmental syndromes associated with the presence of an increased nuchal translucency (NT) thickness (>3 mm) in the first trimester of pregnancy.

Increased nuchal translucency in the presence of normal chromosomes: what's next?

Purpose of review First trimester screening is presently offered to all pregnant women as a means of prenatal screening for Down syndrome, trisomy 18, and trisomy 13. Nuchal translucency measurement is a fundamental component of the screening protocol. A woman whose fetus’ nuchal translucency is greater than the 95th percentile is also at increased risk for a multiplicity of other adverse pregnancy and pediatric outcomes, and as a consequence, counseling of patients about their testing options and range of pregnancy outcomes has become complex and difficult. Recent findings The increased risk for chromosome abnormalities, congenital heart malformations, and pregnancy loss in the presence of an increased nuchal translucency is well documented. What has not been clearly defined is the incidence of other genetic syndromes, congenital defects, and adverse pregnancy and pediatric outcomes in the presence of increased nuchal translucency. Currently, Noonan syndrome is the only molecular genetic condition that has been shown to have a clear association with the finding of increased nuchal translucency in the first trimester. Summary This article reviews the current literature on outcomes in pregnancies with an increased nuchal translucency and a normal karyotype. We summarize the range of outcomes detected in the first trimester with recommendations for further prenatal testing and counseling of patients.

Diagnostic exome sequencing for patients with a family history of consanguinity: over 38% of positive results are not autosomal recessive pattern.

Diagnostic exome sequencing (DES) is an effective tool for diagnosis in intractable cases where the underlying cause is thought be genetic. It is commonly assumed that patients with a family history of consanguinity will have increased detection rates for rare autosomal recessive Mendelian disorders through DES. Herein, we analyzed the diagnostic yield and relevant inheritance patterns within the DES cases with a reported consanguineous family history. Of the first 500 unselected cases referred for DES, 40 (8.0%) had a known consanguineous family history. Among the 40 cases, 13 (32.5%) received a definitive molecular diagnosis through DES and such positive rate is similar to that of families with no reported consanguinity (139/460, 30.2%, P=0.63). Although homozygous alterations likely related to consanguinity have been identified in eight positive cases, the other five (38.4%) causative mutations were unrelated to autosomal recessive inheritance. Our retrospective analysis demonstrated that individuals with known consanguinity were not more likely to have a positive DES result and a significant portion of the positive findings were not within an autosomal recessive gene. These results highlight that all applicable inheritance patterns should be considered for patients with a known family history of consanguinity.

Response to “Half of first trimester screen positive pregnancies with an abnormal karyotype had a normal nuchal translucency measurement”

Response to “Half of first trimester screen positive pregnancies with an abnormal karyotype had a normal nuchal translucency measurement” Christina Alamillo, David Krantz, Mark Evans, Morris Fiddler and Eugene Pergament Prenatal Diagnosis 2013:33:811. DOI: 10.1002/pd.4187 The authors wish to bring to readers’ attention a typographical error in the aforementioned paper. Second paragraph, last sentence ... “None (0%) of the remaining fourteen chromosome abnormalities, including one case of trisomy 16, two cases of triploidy, one case of 70,XXYY, five mosaic trisomies, and five chromosome rearrangements had NT measurements 3.0mm (Table 1).” The authors would like to apologize for this error and any confusion it may have caused.

Clinical whole-exome sequencing results impact medical management

Clinical diagnostic whole‐exome sequencing (WES) is a powerful tool for patients with undiagnosed genetic disorders. To demonstrate the clinical utility, we surveyed healthcare providers (HCP) about changes in medical management and treatment, diagnostic testing, reproductive planning, and use of educational services subsequent to WES testing.

Post Mortem Diagnostic Exome Sequencing Identifies a de novo TUBB3 Alteration in a Newborn with Prenatally Diagnosed Hydrocephalus and Suspected Walker-Warburg Syndrome.

OBJECTIVE Herein we report a case of a deceased newborn with prenatally detected hydrocephalus. Postnatal findings included abnormal brain imaging and electroencephalogram (EEG), optic nerve abnormalities, and elevated creatine kinase (CK). No underlying genetic etiology had been previously identified for the proband, despite testing with a congenital muscular dystrophy gene panel. METHODS Diagnostic exome sequencing (DES) was performed on the proband-parents trio, and candidate alterations were confirmed using automated fluorescence dideoxy sequencing. RESULTS Exome sequencing of the proband, mother and father identified a previously unreported apparently de novo heterozygous tubulin, beta-3 (TUBB3) c.523G>C (p.V175L) alteration in the proband. CONCLUSION Overall, DES established a likely molecular genetic diagnosis for a post-mortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis, to be available to the parents in future pregnancies.

Authors' response regarding genetic assessment following increased nuchal translucency and normal karyotype

The statements by Briere et al. in their Letter to the Editor regarding our article (‘Genetic assessment following increased nuchal translucency and normal karyotype,’ Pergament et al.) raises important issues concerning the interpretation and genetic counseling in the case of sequence variations whose causal relationships to clinical phenotype are unclear. These authors are clear in their belief that the mutation in question – P655L (c.1964C->T) in gene, SOS1 – should be considered as a ‘benign’ mutation and, thus, presumably reported as such to patients who carry this variation. They base this interpretation on reports, including one that involved the work of two of three current authors of the Letter to the Editor, in which individuals first identified as affected with the clinical constellation comprising Noonan syndrome were found on genetic testing to carry this mutation as did an unaffected parent. We recognize that our paper will ultimately be judged on how the data derived from molecular testing is both presented and discussed with pregnant patients in order for them to make meaningful reproductive decisions, ambiguous as that information may at times be. We disagree with the certainty of labeling this a benign mutation and take a conservative approach for the following reasons: Our genetic testing was based on a prenatal population known to be at-risk for Noonan syndrome – and other conditions – because of increased nuchal translucency (>3mm) and a normal karyotype. This informative population is potentially different from those of previous reports of Noonan syndrome and SOS1/P655L, which were based on a clinical diagnosis first. We did not, at the time of publication, have sufficient follow-up data on the births and subsequent health of the babies born who had been found to be carrying the mutation. And until such time as this data are collected and analyzed, we believe it is most responsible to counsel these at-risk parents with the broadest set of information the experience of investigators can provide them. Genotype–phenotype correlations have yet to be fully defined in the case of Noonan syndrome. Whereas an affected parent reportedly is found in 30% to 75% of postnatal diagnoses, in the prenatal period the proportion of de novo mutations versus familial mutations leading to Noonan syndrome has not been defined. Given the great variability in clinical characteristics, including facial phenotype changes with age resulting in less pronounced features in adults, questions of penetrance and variable expressivity in Noonan syndrome accompany interpretation of laboratory data. These terms capture both the state of our understanding of genotype–phenotype relationships in Noonan syndrome as well as provide prospective parents the most complete translation of the literature upon which genetic counseling is based. As dissatisfying as these concepts are to medical geneticists and patients, penetrance and variable expressivity would account for a mutation to be present both in affected offspring and unaffected parents. We did represent data in our paper as ‘Affected,’ (Table 2) but do point out that label was footnoted with P655L described as demonstrating ‘variable clinical expressivity.’ This was based primarily on the statement of Roberts et al. that ‘we cannot be sure if P655L . . ...[is] the result of bona fide mutation[s] or polymorphism[s]’ and that proband 10 in their Table 1 was described as having hydronephrosis and required special education. If we remove the two fetuses with this sequence variation from the data, it lowers the percentage of Noonan cases to 5%. In our continuing use of this molecular panel for pregnancies with increased nuchal translucency and a normal karyotype, now over 350 cases, the frequency of the P655L sequence variation is 1.3%, somewhat less than what the authors cited in their laboratory experience when screening patients diagnosed with Noonan syndrome. The overall frequency of mutations associated with Noonan syndrome, less this variant, remains at approximately 5%. The clinical significance of the P655L sequence variation in this prenatal population, however, remains to be determined in postnatal follow-up. An unresolved issue in our minds is an acceptable standard or process for defining, interpreting, and reporting of sequence variations when Noonan syndrome is involved. The Molecular Subcommittee of the American College of Medical Genetics Laboratory Quality Assurance Committee has published a ‘decision tree’ for interpretation of sequence variants and clinical reporting, including a list of evidential studies that should be used to support sequence variant interpretation (Figure 1). These should be fully applied in the case of the P655L sequence variation as performed on other SOS1 mutations. The ACMG Standards and Guidelines (2008) does state, ‘Variants of unknown clinical significance, whether believed to be benign or not, must be included in the report and followed by the laboratory’s interpretation of the likely clinical significance’. In turn, the language used to communicate the meaning of molecular findings to healthcare providers and their patients has become increasingly complex and challenging. Although the first case (April 25, 2010) reported that the fetus was predicted to be affected with Noonan syndrome, subsequent reports evolved from concluding that the finding of P655L in the SOS1 gene ‘is currently considered by this laboratory to be a variant of uncertain significance’ (27 April 2010) to our present conclusion that ‘P655L in the SOS1 gene has been previously