Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights.

Micro and Martsolf syndromes are rare clinically and genetically overlapping disorders caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. We describe 34 new patients, 27 with Micro and seven with Martsolf. Patients presented with the characteristic clinical manifestations of the two syndromes, including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. Brain imaging showed in the majority of cases polymicrogyria, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Unusual additional findings were pectus excavatum (four patients), pectus carinatum (three patients), congenital heart disease (three patients) and bilateral calcification in basal ganglia (one patient). Mutational analysis of RAB3GAP1 and RAB3GAP2 revealed 21 mutations, including 14 novel variants. RAB3GAP1 mutations were identified in 22 patients with Micro, including a deletion of the entire gene in one patient. On the other hand, RAB3GAP2 mutations were identified in two patients with Micro and all Martsolf patients. Moreover, exome sequencing unraveled a TBC1D20 mutation in an additional family with Micro syndrome. Our results expand the phenotypic and mutational spectrum associated with Micro and Martsolf syndromes. Due to the overlapped severities and genetic basis of both syndromes, we suggest to be comprehended as one entity "Micro/Martsolf spectrum" or "RAB18 deficiency."

A novel WNT10A mutation causes non-syndromic hypodontia in an Egyptian family.

OBJECTIVE: Tooth agenesis is the most common dental anomaly, whose aetiology still remains to be fully elucidated. The aim of this study was to investigate the genetic cause of non-syndromic hypodontia with clinical variability in an Egyptian family. DESIGN: The entire coding regions including exon-intron boundaries of the MSX1, PAX9 and WNT10A genes were investigated by direct sequencing in all affected family members. RESULTS: Novel heterozygous mutation inherited in an autosomal dominant manner was identified in the WNT10A gene. This 21-bp deletion combined with 1-bp insertion, c.-14_7delinsC, eliminates the translation initiation codon leading to either no protein production or translation of alternative open reading frames. None of the control subjects (400 chromosomes) were carriers of this novel WNT10A mutation. No pathogenic mutations were found in the MSX1 and PAX9 genes. CONCLUSIONS: The novel c.-14_7delinsC mutation might be the etiological variant of the WNT10A gene responsible for the permanent tooth agenesis in the Egyptian family. WNT10A is a major candidate gene for non-syndromic hypodontia.

Maternal serum alpha fetoprotein among pregnant females in Alexandria.

UNLABELLED: Maternal serum alpha fetoprotein (MSAFP) was introduced as a screening test for congenital malformations especially neural tube defects (NTDs) two decades ago. However, many factors were known to affect its level. From these are racial differences and maternal weight. The aim of the present work is to illustrate the normal distribution of MSAFP among working pregnant women in Alexandria in gestational age 16-18 weeks, to identify some of its determinants, and to determine the specificity and sensitivity of MSAFP for the detection of congenital anomalies and adverse pregnancy outcome. MATERIAL AND METHODS: A sample of 608 pregnant working women who were 16-18 week gestation was recruited for the study from the antenatal clinic affiliated to Gamal Abdel Nasser Health Insurance Hospital in Alexandria. The enrolled women were interviewed using a structured questionnaire and a blood sample was collected from each of them to measure the level of MSAFP. At the expected time of delivery, Gamal Abd el Nasser Health Insurance Hospital was visited to collect data about the outcome of pregnancy of the enrolled women. RESULTS: The median of MSAFP level for deliveries with no congenital anomalies were 25.5, 33.5, and 53.2 IU/ml, at gestational weeks 16, 17 and 18 respectively. The significant variables related positively to MSAFP level included abortion or stillbirth, congenital anomalies in the index pregnancy, gestational age, bleeding during pregnancy, gestational diabetes, twin pregnancy, consanguinity between maternal parents, history of congenital or genetic diseases in maternal family, and caesarian section deliveries. Fatigue score was negatively correlated to MSAFP level. Using MSAFP multiples of median (MOM), 42.9 % of abortions and stillbirths, 57.1 % of twin pregnancies, 31.25 % of preterm deliveries and 27.3 % of low birth weight had levels of 3 MOM or more. One fourth of the congenital anomalies were below 0.5 MOM and 41.7 % were at or above 3 MOM. The sensitivity of MSAFP test for the detection of NTDs (cutoff point 2.5+ MOM) or Down syndrome (cutoff point <0.5 MOM) among the study sample was 100% (CI: 19.8-100%). Specificity for NTDs was 92.7% (CI: 90.3-94.6%), while the specificity for Down syndrome was 89.1% (86.3-91.4%). The sensitivity for adverse pregnancy outcome (cutoff point <0.5 or 2.5+ MOM) was 41.6, and the specificity was 85.8%. In conclusion, the cutoff points of MSAFP of the study sample are different from those for other populations. Different factors affect the level of MSAFP including adverse pregnancy outcomes. It is recommended to introduce antenatal screening for congenital anomalies as a routine screening test during pregnancy using levels adapted from the local population for cutoff point determination.