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BackgroundThe causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.MethodsRetrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.ResultsBetween 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).ConclusionsMolecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

Objective  The aim of this study is to evaluate high-risk pregnant females' offspring as regard the presence of any medical condition, hereditary disorder, or major anomaly as well as to document parental sociodemographic characteristics and compliance with follow-up schedules of fetal medicine and clinical genetic clinics. Study Design  This prospective 2-year cohort study of neonates and infants reported the referral indications, investigations, and diagnoses obtained through prenatal and postnatal examinations. It also reported their parental follow-up vigilance. Results  Of the 811 infants of high risk females referred 460 (56.7%) came for assessment. Mean parental consanguinity and endogamy were 67 and 71.3%, respectively. All pregnant mothers underwent first-trimester biochemical testing (plasma protein-A, α-fetoprotein [AFP], human chorionic gonadotropin [hCG]) and serial ultrasound examinations. Seventy mothers needed second-trimester biochemical testing (AFP, hCG, and estriol). Sixty-two mothers underwent amniocentesis where G-banding karyotype, fluorescence in situ hybridization and targeted molecular testing for the specific gene mutation of single gene disorders were conducted according to suspected disorders. High quality fetal ultrasound was performed when brain malformations were suspected, while 16 fetuses required brain MRI examination. Mean age of newborns at first examination was 26.5 days. They were grouped according to the maternal indication for referral. Upon examination, 18 neonates had confirmed congenital malformations/genetic disorders. Five of them were diagnosed prenatally. In four other fetuses with single gene disorder, the molecular diagnosis of their affected siblings was not established prior to this pregnancy; thus, prenatal diagnosis was not possible. The remaining nine cases were diagnosed postnatally. Conclusion  Parental consanguinity and endogamy were increased among high-risk pregnancies. Public awareness about potential adverse effects of consanguineous marriages and the importance of genetic testing are imperative. A structured multidisciplinary team of specialists in fetal medicine, clinical genetics, and neonatology provides good genetic services. Expansion and financial support of these services are urgently required. Key Points A multidisciplinary team provides good genetic services in high-risk pregnancies. Parental consanguinity and endogamy are increased among high-risk pregnancies. Increased public awareness about genetic testing importance and financial support are imperative. [ABSTRACT FROM AUTHOR]

We report two unrelated boys with frontonasal dysplasias type‐2 (FND‐2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele‐like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed. [ABSTRACT FROM AUTHOR]

Objective: Folic acid insufficiency is a known risk factor for neural tube defects (NTDs), while the role of vitamin B12 is questionable. Thus, our purpose was to investigate whether low maternal serum vitamin B12 is associated with an increased risk of NTDs., Setting: Prenatal Diagnosis and Clinical Genetics Clinics, National Research Centre, in collaboration with the Radioisotope Department, Nuclear Research Centre, Cairo., Materials and Methods: The study groups included 36 women who were, or had been, pregnant with a NTD-affected fetus. The control groups comprised 35 healthy women with normal prior or current pregnancy and uncomplicated obstetric histories. Fasting plasma homocysteine, serum folate and cobalamin (vitamin B12) were determined. Odds ratio (OR) and 95% confidence intervals were calculated., Results: The fasting homocysteine was significantly higher in the study groups as compared to the controls. The median serum folate concentrations were similar in cases and controls, while the median vitamin B12 concentrations were significantly lower in the study groups compared to the controls. Low vitamin B12 concentration was associated with an approximately 2- to 3-fold increased risk for NTDs., Conclusion: Low maternal serum values of vitamin B12 can be considered an important etiologic factor for the development of neural tube defects in our population. This may help in both genetic counseling for families with a history of NTD malformation, and as a pre-conceptional prophylactic measure by maternal supplementation of vitamin B12 and folic acid.