USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Genetics of syndromic and nonsyndromic aortopathies.

PURPOSE OF REVIEW: To review the literature and provide a summary of management of syndromic and nonsyndromic aortopathies. RECENT FINDINGS: The number of newly identified genetic causes for aortopathies have continued to increase over the past 10 years. The number of reported individuals with most hereditary aneurysm genes is small but increasing with more publications focusing describing the natural history caused by each gene. SUMMARY: Aortopathy can present as an isolated finding or present as part of a larger genetic syndrome. Advances in genetic testing technology has shed light on the increasing importance of molecular diagnostics in the evaluation and management of patients with hereditary aortic disease. Molecular diagnostics and family phenotyping can aide in the diagnosis and management of pediatric patients with aortic disease.

MAT2A mutations predispose individuals to thoracic aortic aneurysms.

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

RATIONALE: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families. OBJECTIVES: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections. METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections. CONCLUSIONS: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

NOD2-associated autoinflammatory disease: a large cohort study.

OBJECTIVE: The aims of the study were to characterize the genotype profile of nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease (NAID) and to report an extended study of the disease. METHODS: A total of 143 adult patients presented with clinical phenotypes suspicious for NAID and all were genotyped for NOD2 sequence variants. The genotype frequencies were compared between our cohort and literature reports. These patients were divided into two groups predicated on the presence or absence of NOD2 variants. RESULTS: Of the 143 patients, 67 (47%) carry NOD2 variants; the genotype frequency was significantly higher among our cohort than in the historical healthy controls. Fifty-four of the 67 carriers of NOD2 variants had NAID, which has a genotype profile that is somewhat different from Crohn's disease. All NAID patients were non-Jewish whites and 69% were women. The median age at onset was 33.5 years and the median disease duration at diagnosis was 10.7 years. NAID was sporadic in 93% of cases. Patients typically presented with periodic fever, dermatitis and inflammatory arthritis. As compared with the NOD2 variant-negative patients, the skin disease more typically manifested as erythematous patches or plaques on the trunk. Oligopolyarthritis/-arthralgia was common, with characteristic distal lower extremity swelling. Associated NOD2 variants were primarily IVS8(+158) or compound IVS8(+158) and R702W. CONCLUSION: This study underscores the NOD2 genotype association with NAID, which is a genetically complex multisystem disorder. It differs phenotypically from Crohn's disease with a distinct genotype profile. This disease may be more common than initially thought.

Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFß pathway. Other syndromes associated with abnormalities in TGFß signaling include Marfan syndrome, Loeys-Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.

Systemic connective tissue features in women with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease associated with hypertension, headache, dissection, stroke, and aneurysm. The etiology is unknown but hypothesized to involve genetic and environmental components. Previous studies suggest a possible overlap of FMD with other connective tissue diseases that present with dissections and aneurysms. The aim of this study was to investigate the prevalence of connective tissue physical features in FMD. A total of 142 FMD patients were consecutively enrolled at a single referral center (97.9% female, 92.1% of whom had multifocal FMD). Data are reported for 139 female patients. Moderately severe myopia (29.1%), high palate (33.1%), dental crowding (29.7%), and early-onset arthritis (15.6%) were prevalent features. Classic connective features such as hypertelorism, cleft palate, and hypermobility were uncommon. The frequency of systemic connective tissue features was compared between FMD patients with a high vascular risk profile (having had ⩾1 dissection and/or ⩾2 aneurysms) and those with a standard vascular risk profile. A history of spontaneous pneumothorax (5.9% high risk vs 0% standard risk) and atrophic scarring (17.6% high risk vs 6.8% standard risk) were significantly more prevalent in the high risk group, p<0.05. High palate was observed in 43.1% of the high risk group versus 27.3% in the standard risk group, p=0.055. In conclusion, in a cohort of women with FMD, there was a prevalence of moderately severe myopia, high palate, dental crowding, and early-onset osteoarthritis. However, a characteristic phenotype was not discovered. Several connective tissue features such as high palate and pneumothorax were more prominent among FMD patients with a high vascular risk profile.

Evolving Approaches to Genetic Evaluation of Specific Cardiomyopathies.

The understanding of the genetic basis of cardiomyopathy has expanded significantly over the past 2 decades. The increasing availability, shortening diagnostic time, and lowering costs of genetic testing have provided researchers and physicians with the opportunity to identify the underlying genetic determinants for thousands of genetic disorders, including inherited cardiomyopathies, in effort to improve patient morbidities and mortality. As such, genetic testing has advanced from basic scientific research to clinical application and has been incorporated as part of patient evaluations for suspected inherited cardiomyopathies. Genetic evaluation framework of inherited cardiomyopathies typically encompasses careful evaluation of family history, genetic counseling, clinical screening of family members, and if appropriate, molecular genetic testing. This review summarizes the genetics, current guideline recommendations, and evidence supporting the genetic evaluation framework of five hereditary forms of cardiomyopathy: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), and left ventricular noncompaction (LVNC).

Treatment of a patient with vertebral and subclavian aneurysms in the setting of a TGFBR2 mutation.

We present the case of a patient diagnosed with hypermobile Ehlers-Danlos syndrome with aneurysms of the subclavian and vertebral arteries. Molecular testing demonstrated transforming growth factor-beta receptor type 2 mutation. She was not a candidate for an open repair; therefore, a hybrid approach involving right vertebral ligation and bypass from the right common carotid to the vertebral C1-2 interface, endovascular exclusion of the left vertebral artery, and stent grafting of the left subclavian/axillary artery was used. The left vertebral embolization proved ineffective, requiring a right-to-left vertebral catheterization with glue occlusion. Based on her proper molecular diagnosis, she underwent prophylactic root and ascending aortic repair.

Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives.

BACKGROUND: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient. METHODS AND RESULTS: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P < .0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P < .0001; ascending: OR, 2.9; P < .001; thoracic: OR, 2.2; P = .01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P = .0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P = .03). CONCLUSIONS: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient's management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members.

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I.

We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected.

Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia.

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-ß receptor 1 and 2 (TGFßR1 and TGFßR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFßR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFßR1 gene, a finding which merits further investigation.

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.

Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.

BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role. METHODS AND RESULTS: By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences. CONCLUSION: We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.

Cutis marmorata telangiectatica congenita: a focus on its diagnosis, ophthalmic anomalies, and possible etiologic factors.

Purpose: Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder typified by localized or generalized cutaneous vascular anomalies, which dissipate over time. We review the diagnostic approach to CMTC and present a comprehensive examination of its ocular manifestations. Additionally, we offer recommendations for the ophthalmologic workup for patients with CMTC. Finally, we examine the possible causes of CMTC and summarize the current efforts to establish an etiologic mechanism for this disease.Methods: Thirty-three published cases of CMTC with ocular anomalies are examined in detail.Results: CMTC is diagnosed based on a specific set of congenital cutaneous symptoms, principally congenital reticular erythema that is unresponsive to local warming and absence of venectasia within the skin lesions. Ocular findings are not currently employed in this diagnostic process, likely due to an incomplete understanding into their presentation, frequency, and natural history. We show that the majority of ophthalmic manifestations are congenital, with glaucoma and posterior segment anomalies, consisting of retinal perfusion defects and vascular abnormalities, as the most frequently reported findings. Typical ophthalmic medical and surgical interventions appear to be effective for management of these CMTC-related pathology. Unfortunately, the etiology and pathophysiology of CMTC remains unknown, which obfuscates efforts to identify, examine, and initiate treatment in patients.Conclusions: While the ophthalmic community has traditionally viewed glaucoma as the classic ocular anomaly of CMTC, this dataset advocates for the prompt investigation of posterior segment abnormalities as well. However, our understanding of CMTC's ocular anomalies is complicated by a lack of reporting and/or incomplete (or nonexistent) ophthalmic examinations, and we strongly encourage comprehensive ophthalmic examinations for all CMTC patients at the time of diagnosis, followed by appropriate screening and surveillance throughout life. We believe these recommendations will spur additional data and disease insights that may be useful for future refinements to CMTC diagnostic algorithms.

Patient education and informed consent for preimplantation genetic diagnosis: health literacy for genetics and assisted reproductive technology.

PURPOSE: Innovative applications of genetic testing have emerged within the field of assisted reproductive technology through preimplantation genetic diagnosis. As in all forms of genetic testing, adequate genetic counseling and informed consent are critical. Despite the growing recognition of the role of informed consent in genetic testing, there is little data available about how this process occurs in the setting of preimplantation genetic diagnosis. METHODS: A cross-sectional study of in vitro fertilization clinics offering preimplantation genetic diagnosis in the United States was conducted to assess patient education and informed consent practices. Descriptive data were collected with a self-administered survey instrument. RESULTS: More than half of the clinics offering preimplantation genetic diagnosis required genetic counseling before preimplantation genetic diagnosis (56%). Genetic counseling was typically performed by certified genetic counselors (84%). Less than half (37%) of the clinics required a separate informed consent process for genetic testing of embryonic cells. At a majority of those clinics requiring a separate informed consent for genetic testing (54%), informed consent for preimplantation genetic diagnosis and genetic testing took place as a single event before beginning in vitro fertilization procedures. CONCLUSIONS: The results suggest that patient education and informed consent practices for preimplantation genetic diagnosis have yet to be standardized. These findings warrant the establishment of professional guidelines for patient education and informed consent specific to embryonic genetic testing.