Main findings
A total of 10 variation sequences of 7 genes were detected in these 14
cases, all of which were in heterozygous state, including 2 pathogenic
variants, 4 likely pathogenic variants and 4 uncertain variants. Of the
14 cases, 4 cases were definitively diagnosed and classified as positive
cases, with a definite diagnosis rate of 28.6% (n=4/14).Normand Ea. Et
al. performed total exome sequencing on 146 prenatal samples, and
molecular diagnosis was performed in 46 of them, with a diagnosis rate
of 32%.8Fu M et al. performed total external
sequencing on 19 abortive tissues, and a total of 36 variation sequences
were detected, among which 12 were pathogenicity variants, with a
diagnostic rate of 33%.9The diagnostic rates in this
study are in line with those of 22-36% in previous large studies.5The four patients with positive results, including
six variants, offered diagnoses including short rib dysplasia type 3,
autosomal dominant polycystic kidney disease type 4, and Alagille
syndrome. Among the positive cases, except case 2, which had autosomal
dominant disease and the variation was from the mother, the remaining 3
cases had autosomal recessive disease and both parents were carriers of
the genetic variation.
Alagille syndrome (ALGS) is an autosomal dominant inherited disease,
which can be caused by a variety of mutations in JAG1 gene
(including complete gene deletion, missense mutation, splice site
mutation, senseless mutation, etc.),10 indicating that
insufficient haploidy of JAG 1 gene can cause the pathogenic cause
of ALGS clinical phenotype.11, 12JAG1 gene
encodes the surface ligand JAG1 , which is a highly conserved
Notch signaling pathway. 13, 14The ligand interacts
with Notch receptor to regulate gene transcription and plays a key role
in cell development and multi-organ system formation.10, 15, 16Case 2 reported that c.2078-2079delGT
mutation of JAG1 gene was splicing mutation, which would lead to
premature translation termination codon and function loss, resulting in
insufficient haploidy of JAG1 gene, leading to clinical
phenotypes related to Alagille syndrome. The main clinical features of
ALGS include liver and heart disease, butterfly vertebrae, and specific
facial features (triangular face, pointed chin). In addition to these
features, most patients also have renal and vascular
abnormalities.17-19 In the fetuses diagnosed with
Alagille syndrome, there were obvious renal abnormalities and other
sonographic phenotypes, which were consistent with the neonatal
phenotype of ALGS
Cases 5 and 7:Two cases of sonographic features all have four short
limbs which development, chest is narrow, and there are abnormal heart
development, including 5 cases and refers to much and toe deformity,
this is completely in line with short rib dysplasia type 3 typical
sonographic features (shorten long bone, thoracic stenosis, occasionally
means more, can also be involved in heart, liver, brain and other system
exceptions).20Short-costal dysplasia type 3 is a
common autosomal recessive osteochondrodysplasia disorder, and theDYNC2HI gene variant is associated with Short-costal dysplasia
type 3 syndrome. 21The DYNC2H1 gene, located at
11q22.3, encodes the heavy chain of cytoplasmic dynamin 2, which is
involved in flagella transport and affects chondrocyte
maturation.22, 23 At the same time, DYNC2H1gene defect leads to the interruption of Hedgehog signaling pathway,
thus affecting the proliferation and differentiation of osteoblasts and
chondrocytes, leading to chondrodysplasia.24, 25
The whole exon sequencing results of Case 1 indicated that the patient
was a repeated compound heterozygous variant of the PKHD1 gene C.
8301delC (p.Asn2768FS) and exon 57-60, which was associated with type 4
phenotype of autosomal recessive polycystic kidney disease. In addition,
ultrasonography suggested that the fetal renal volume was increased,
suggesting that the infant polycystic kidney was considered. In case 4,
ultrasound showed abnormal development of thoracic vertebrae, cleft lip
and palate, congenital abnormal development of heart: Tetralogy of
Fallot, single umbilical artery. Whole exome sequencing detectedGLA gene and Nodal gene variation. Fabry disease caused byGLA gene c.61C>G heterozygous variation can cause
heart, kidney and cerebrovascular diseases, while visceral ectopia
caused by Nodal gene variation can lead to abnormal trunk development
and severe congenital heart defect. The disease caused by this mutation
can explain part of the clinical phenotype of the abortive tissue.
Although it cannot be classified as a positive case, it can explain the
related reasons of the abortive phenotype. Further functional analysis
can be carried out to clarify the role of this mutation site.
Heterozygous variation of GJB2 gene c.176_191del (p.G59fs) was
detected in the fetus of case 9. According to the laboratory
classification standard, this mutation was identified as pathogenicity
variation, which originated from the father. The pregnant woman in Case
10 had a history of two abortions, and the aborted tissue had not been
tested for relevant genes before. In the whole exon sequencing of the
flow product, the heterozygous mutation of F5 gene (c.
4964C>T) was found, which could lead to the related
phenotypes of recurrent abortion susceptibility type 1 and factor V
deficiency.