Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.

Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.

Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center’s experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) ( p = 0.004). WES yield was relatively high (42.9–60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.

Following the observation detected in a previous study that X chromosome monosomy in Turner’s syndrome genotypes was associated with a sporadic loss and/or gain of other chromosomes, we studied here whether this instability is a consistent finding in constitutional autosomal trisomies. We used PHA-stimulated lymphocytes derived from 14 patients (10 patients with trisomy 21, 2 with trisomy 18, and 2 with trisomy 13). Fourteen healthy controls were compared. Fluorescence in situ hybridization, applied at interphase cells, was used to evaluate the level of aneuploidy for 3 randomly selected chromosomes (autosomes 8, 15, and 16) in each sample. For each tested chromosome, our results showed a significantly higher level of aneuploid cells in the samples from the patients than in those from controls, with no difference between the patient groups. The mean level of aneuploid cells (percentage) for all 3 tested autosomes was almost twice as high in the patient samples as in the control samples. The aneuploidy level was mainly due to monosomy, which was significantly higher in the samples from the patients than in those from controls for each one of the tested chromosomes, with no difference between the patient groups. The mean level of monosomic cells (percentage) for all 3 tested chromosomes was almost twice as high in the patient samples as in the control samples. Our study shows that various constitutional autosomal trisomies are associated with an increased frequency of non-chromosome specific aneuploidy and is a continuation of the previous study documenting sporadic aneuploidy in Turner’s sample cells. It is possible that primary aneuploid cells destabilize their own genome resulting in variable aneuploidy of other chromosomes. It is also possible that one or several common factor(s) is/are involved in both constitutional and sporadic aneuploidy.