The past, present and future of service delivery in genetic counseling: Keeping up in the era of precision medicine.

Precision medicine aims to approach disease treatment and prevention with consideration of the variability in genes, environment, and lifestyle for each person. This focus on the individual is also key to the practice of genetic counseling, whereby foundational professional values prioritize informed and autonomous patient decisions regarding their genetic health. Genetic counselors are ideally suited to help realize the goals of the precision medicine. However, a limited genetic counseling workforce at a time in which there is a rapidly growing need for services is challenging the balance of supply and demand. This article provides historical context to better understand what has informed traditional models of genetic counseling and considers some of the current forces that require genetic counselors to adapt their practice. New service delivery models can improve access to genetic healthcare by overcoming geographical barriers, allowing genetic counselors to see a higher volume of patients and supporting other healthcare providers to better provide genetic services to meet the needs of their patients. Approaches to genetic counseling service delivery are considered with a forward focus to the challenges and opportunities that lie ahead for genetic counselors in this age of precision health.

A novel approach in pediatric telegenetic services: geneticist, pediatrician and genetic counselor team.

PurposeOur aim was to improve access to genetic services in an underserved region by developing a collaborative telegenetic service delivery model with a pediatrician, medical geneticist, and genetics counselor (GC).MethodsProtocols for the evaluation of common genetic indications were developed. Patients referred with indications suggestive of a syndromic etiology were scheduled to see the geneticist directly via telegenetics. Other patients were scheduled to see the pediatrician and GC in person before follow-up with the geneticist if indicated. Patients seen by the geneticist and/or pediatrician/GC were enumerated and the next available appointment was tracked. Patient satisfaction surveys were conducted.ResultsOf the 265 patients evaluated during the study period, 116 (44%) were evaluated by a pediatrician and GC in person first, after which 82 (71% of those evaluated) required further follow-up with the geneticist. The next available appointment with a pediatrician and GC never exceeded 6 weeks, while new appointments with a geneticist ranged from 3 to 9 months. All patients reported high satisfaction with this genetic service model.ConclusionThe pediatrician/GC clinic provides a model of collaborative care that is a medical home neighbor and exemplifies the integration of genetics into primary care. The telegenetics clinic offers a viable solution to providing competent and convenient access to a geneticist for patients in chronically underserved regions.

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease.

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

Implementing a Protocol to Optimize Detection of Chromosome Abnormalities in Cases of Miscarriage or Stillbirth at a Midwestern Teaching Hospital.

CONTEXT: Results from chromosome testing after spontaneous abortion (SAB) or intrauterine fetal demise (IUFD) are useful in patient counseling; however, results can be inconclusive when cell cultures for chromosomes are unable to grow from products of conception. Chromosomal microarray analysis (CMA) can analyze DNA from nonviable fetal tissue. OBJECTIVE: To examine whether establishing a genetic testing protocol for karyotype and CMA on SAB and IUFD tissues increases diagnostic yield. DESIGN: A retrospective chart review was conducted in cases of SAB or IUFD when karyotyping and/or CMA was requested, comparing two periods: Preprotocol and postprotocol implementation. MAIN OUTCOME MEASURES: Diagnostic yield was compared by using the number of determinate test results in the preprotocol and postprotocol study periods. A case was considered to have indeterminate results when the final genetic test results reported no fetal tissue or no cell culture growth. RESULTS: A total of 55 preprotocol and 52 postprotocol patients were analyzed. Diagnostic yield increased from 72.7% to 94.2% after implementation of the genetic testing protocol (p = 0.0004). Indeterminate results occurred more frequently before compared with after implementation of the protocol. CONCLUSION: A protocol of reflexing to CMA or proceeding directly with CMA gives a higher diagnostic yield in the genetic evaluation of SAB or IUFD. Institutions should consider implementing a genetic testing protocol to improve diagnostic yield. Our study results emphasize the importance of proceeding directly to microarray analysis and give support for current clinical recommendations for genetic testing after fetal demise.

Serotonergic candidate genes and puerperal psychosis: an association study.

BACKGROUND: Altered serotonergic function is implicated in the aetiology and pathogenesis of a host of psychiatric disorders, and structural variations/polymorphisms in genes encoding the serotonin transporter and various serotonin receptor subtypes are attractive candidates to investigate the biological component underlying these disorders. Specific phenotypic subtypes, that perhaps represent homogeneous forms of the disorder, may increase the power to detect genes in complex diseases. OBJECTIVE: We investigated regulatory and functional polymorphic DNA markers of serotonergic candidate genes using a case-control approach in puerperal psychosis and bipolar affective disorder probands. METHODS: We genotyped 320 female participants (104 puerperal psychosis probands, 102 bipolar disorder participants and 114 controls) at the serotonin transporter SERT (5-HTT) 5-HTTVNTR and 5-HTTLPR locus; serotonin receptor 2A (5-HT2A)-T102C and His452Tyr loci, the serotonin receptor 2C (5-HT2C)-Cys23Ser locus, and seven unrelated Alu polymorphic markers. RESULTS: We observed an association of the puerperal psychosis phenotype with the allele 10 of 5-HTTVNTR of SERT (P=0.004) and a modest association with the genotypic frequencies of the 5-HTTLPR (P=0.036). A nominal P value of 0.006 was observed with the S-10 haplotype in the PP group as compared with bipolar affective disorder probands. Significant association was observed with bipolar affective disorder phenotype with Tyr allele of the 5-HT2A His452Tyr gene polymorphism (P=0.00043) even after a conservative multiple test correction. No association was observed, however, with the 5-HT2A T102C locus, and the distribution of the other seven Alu markers did not differ between the groups. CONCLUSION: The association between polymorphisms in serotonergic genes (SERT and 5-HT2A, 5-HT2C) suggests that these genetic factors can modulate vulnerability to puerperal psychosis in female bipolar participants.

MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India.

BACKGROUND: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. METHODS: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. RESULTS: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. CONCLUSIONS: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder.

Does latitude as a zeitgeber affect the course of bipolar affective disorder?

BACKGROUND: Bipolar disorder (BD) is characterized by recurrent episodes of mood dysregulations and depression is considered as the most frequent form of relapse. However, there is some evidence that in tropical countries, the course might be different with fewer depressive episodes. This study aims to examine the frequency of depressive and manic episodes in a sample of subjects with BD from India. METHODS: Index subjects and a reliable informant (a family member) were interviewed with Diagnostic Interview for Genetic studies and a life chart was drawn to ascertain the episodes of illness in addition to reviewing their clinical case records. The mean total episode frequency and the mean manic and depressive episode frequency were estimated for this study. RESULTS: Data on the total episode number and number of manic and depressive episodes separately was available in 439 subjects. The subjects had been ill for 7.45 years, had experienced an average of 3.29 episodes of mania and 1.08 episodes of depression. Thus episodes of mania were seen to be more frequent. CONCLUSION: It has been increasingly recognized that circadian rhythm abnormalities could play an important role in the relapse and symptom expression of bipolar disorder. The mania predominance in the course of BD in this population contrasts from the depressive predominance in other studies. We suggest that this phenomenon could be a function of latitudinal gradient in the expression of BD using the zeitgeber hypothesis.

Evolutionary analysis of PHLPP1 gene in humans and non-human primates.

The chromosome 18q22-23 region has been shown to be implicated in bipolar disorder (BPAD) by several studies. PHLPP1 gene, in the locus (chromosome 18q22-23), is involved in circadian pathways and bears modules like 'PH domain and leucine rich repeat protein phosphatase'. This gene also contains a polyglutamine (CAG or PolyQ) repeat motif at the carboxyl terminal end. A comparative analysis of the PolyQ repeats of the PHLPP1 gene in humans, non-human primates and other species has been attempted in order to investigate the possible significance of repeat length as seen in other triplet-repeat associated diseases. Sequencing of the CAG repeat in humans and in non-human primates revealed that the CAG repeat is not polymorphic in humans; whereas, in other species it shows an area of high variability, both in length and sequence composition. Despite the conservation of circadian clock components in different species, there is remarkable diversity in the protein structure, regulation and biochemical functions of the circadian orthologs. These can be due to specific adaptations in accordance with the physiology of the particular species providing a species-specific biological advantage.

SYNGR1 is associated with schizophrenia and bipolar disorder in southern India.

Chromosome 22q11-13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case-control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP--Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case-control analysis revealed allelic (P = 0.028-0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.