The implications to women of childbearing age taking Warfarin Anticoagulation

Faculty of Health Sciences School of Patholgy 8601804k [email protected] oral anticoagulant, warfarin, when administered in pregnancy, can cause warfarin embryopathy, fetal central nervous system abnormalities, spontaneous abortion and fetal intrauterine death. Women with prosthetic heart valves usually require warfarin in pregnancy because of their high risk for thromboembolic complications. Anticoagulation regimens in pregnancy in these women aim to balance the fetal effects of warfarin with maternal risks of thromboembolism. This study was conducted by structured interview of 124 black urban South African women of childbearing age, who had at least one warfarin-exposed pregnancy. The study aimed to determine the pregnancy outcomes in this cohort, their awareness of the effects of warfarin in pregnancy, and what management practices, as reported by them, had occurred with regard to their anticoagulation in pregnancy and what genetic counselling they had received. There was a significant difference in outcome between warfarin-exposed and non-exposed pregnancies; 55.2% (123/223) of warfarin-exposed pregnancies ended in the birth of an abnormal baby, spontaneous abortion or intrauterine death. The warfarin embryopathy rate was estimated at 4.5 – 5.4%. Most women reported having been given information about warfarin in pregnancy, though their awareness about the personal and fetal effects of warfarin was often inaccurate. Of warfarin-exposed pregnancies, 95% were reportedly exposed during critical weeks six to ten of pregnancy, and >50% after 36 weeks. Only 5/124 (4%) interviewees had genetic counselling. Poor pregnancy outcomes, lack of awareness about the effects of warfarin in pregnancy, and management practices at odds with international regimens are all areas highlighted by this study that require urgent attention in this high-risk group of women

Clinical Outcomes and Counselling Issues regarding Partial Trisomy of Terminal Xp in a Child with Developmental Delay

Female carriers of balanced translocations involving an X chromosome and an autosome offer genetic counselling challenges. This is in view of the number of possible meiotic outcomes, but also due to the impact of X chromosome-localised genes that are no longer subject to gene silencing through the X chromosome inactivation centre. We present a case where delineation of the extent of X chromosome-localised genes on the derivative autosome using molecular karyotyping offers critical information in the context of genetic counselling.

Thyroid dysfunction in a cohort of South African children with Down syndrome

Background. While international studies show thyroid dysfunction occurs more commonly in individuals with Down syndrome (DS) than in the general population, there is a paucity of available data from sub-Saharan Africa.Objectives. To document the range of thyroid function in a cohort of South African children with DS, and to assess referral and treatment practices when thyroid dysfunction was present. Methods. A retrospective file-based study of 391 children with DS seen at the genetic clinics at three Johannesburg hospitals from 2003 to 2008. Thyroid function test (TFT) results (thyroid-stimulating hormone and free thyroxine) and demographic details were collected for each child. Endocrine clinic files from two of the hospitals were reviewed for additional referral and treatment information.Results. The majority (83.6%) of children had at least one TFT, in most cases performed between the ages of 2 and 12 months. The most common form of thyroid dysfunction was subclinical hypothyroidism (SCH) (28.7%). Up to one-third of the patients, including several neonates with abnormal results, were not referred for further evaluation and were therefore not receiving the necessary treatment. Inter- laboratory biochemical discrepancies and lack of population-specific reference ranges complicated the interpretation of results. The controversy surrounding whether, and how, to treat SCH influenced treatment practices. Conclusions. Thyroid dysfunction is prevalent in South African children with DS. There is an urgent need to address the laboratory biochemical discrepancies, and to establish guidelines for surveillance and treatment to prevent further irreversible neurological and physical impairment.

Delineation of 2q32q35 Deletion Phenotypes: Two Apparent “Proximal” and “Distal” Syndromes

We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1–q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6 Mb deletion in patients 1 and 2 and a 24.7 Mb deletion in patient 3. We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2, and CPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene

12q14 Microdeletions: Additional Case Series with Confirmation of a Macrocephaly Region

To date, there have been only a few reports of patients carrying a microdeletion in chromosome 12q14. These patients usually present with pre- and postnatal growth retardation, and developmental delay. Here we report on two additional patients with both genotype and phenotype differences. Similar to previously published cases, one patient has haploinsufficiency of the HMGA2 gene and shows severe short stature and developmental delay. The second patient is only one of a handful without the loss of the HMGA2 gene and shows a much better growth profile, but with absolute macrocephaly. This patient’s deletion is unique and hence defines a likely macrocephaly locus that contributes to the general phenotype characterising the 12q14 syndrome

A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients : findings and recommendations

Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.</p

The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients

Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity

A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations

Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.</p