First identification and isolation of equine herpesvirus type 1 in aborted fetal lung tissues of donkeys.

BACKGROUND: Equine herpesvirus type 1 (EHV-1) is commonly associated with horse abortion. Currently, there are no reported cases of abortion resulting from EHV-1 infection in donkeys. RESULTS: This was the first survey-based study of Chinese donkeys. The presence of EHV-1 was identified by PCR. This survey was conducted in Chabuchar County, North Xinjiang, China, in 2020. A donkey EHV-1 strain (Chabuchar/2020) was successfully isolated in MDBK cells. Seventy-two of 100 donkey sera were able to neutralize the isolated EHV-1. Moreover, the ORF33 sequence of the donkey-origin EHV-1 Chabuchar/2020 strain showed high levels of similarity in both its nucleotide (99.7‒100%) and amino acid (99.5‒100%) sequences, with those of horse EHV-1 strains. EHV-1 Chabuchar/2020 showed significant consistency and was classified within cluster 1 of horse EHV-1 strains. Further, analysis of the expected ORF30 nucleotide sequence revealed that donkey EHV-1 strains contained guanine at position 2254, resulting in a change to aspartic acid at position 752 of the viral DNA polymerase. Therefore, these strains were classified as horse neuropathogenic strains. Lastly, a phylogenetic tree was constructed using the partial ORF68 nucleotide sequences, showing that the identified donkey EHV-1 strain and the EHV-1 strain found in aborted Yili horses in China comprised a novel independent VIII group. CONCLUSION: This study showed the first isolation and identification of EHV-1 as an etiological agent of abortions in donkeys. Further analysis of the ORF33, ORF30, and ORF68 sequences indicated that the donkey EHV-1 contained the neuropathogenic genotype of strains in the VIII group. It is thus important to be aware of EHV-1 infection in the donkey population, even though the virus has only been identified in donkey abortions in China.

Pathologic and Immunohistochemical Evidence of Possible Francisellaceae among Aborted Ovine Fetuses, Uruguay.

The only genus of the Francisellaceae family known to contain species pathogenic to mammals is Francisella, for which reported cases in the Southern Hemisphere have been limited to Australia. We describe severe necrotizing and inflammatory lesions and intralesional immunohistochemical identification of Francisella sp. lipopolysaccharide among aborted ovine fetuses in Uruguay.

[Genetic analysis of a Chinese family affected with α-dystroglycanopathy due to variant of B3GALNT2 gene].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus. METHODS: A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c.261-2A>G and c.536T>C (p.Leu179Pro), which were inherited from its father and mother, respectively.According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM2_Supporting; PM3+PM2_Supporting+PP3+PP4). CONCLUSION: The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.

Ethical Research Involving Fetal Human Subjects.

Fetal tissue research refers to research using several types of tissue, including but not limited to samples obtained from aborted fetuses, cell lines derived from aborted fetuses, and in rarer cases, living previable neonates who have survived an abortion attempt. The ethical questions surrounding each type of tissue procurement are not identical, but do share similarities.This guideline on fetal tissue research discusses the moral status of the human fetus, the state of ethics for medical research on vulnerable subjects, aspects of medical research using human fetal tissue, and the necessity of including fetuses as a protected class under vulnerable populations in research. The debates connected to embryo stem cell research and other research related to embryos are beyond the scope of this document.

Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function.

Stillbirth is the loss of a fetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing fetus. We observed four heterozygous, nonsynonymous variants in transient receptor potential melastatin 7 (TRPM7), a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. We used site-directed mutagenesis and single-cell patch-clamp to analyze the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. Our results show that two TRPM7 variants, p.G179V and p.T860M, lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents; however, siRNA knockdown did not directly affect action potential morphology. TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.

Detection of bovine gammaherpesvirus 6 in tissues of aborted fetuses from dairy cows concomitantly infected by Histophilus somni.

Bovine gammaherpesvirus 6 (BoGHV6), formerly known as bovine lymphotropic virus, is a member of the Macavirus genus, subfamily Gammaherpesvirinae, family Herpesviridae, that was initially associated with proliferative diseases in cattle. While the Macavirus genus contains agents, including alcelaphine gammaherpesvirus 1 (AlGHV1), ovine gammaherpesvirus 2 (OvGHV2), and caprine gammaherpesvirus-2 (CpGHV2), known to cause malignant catarrhal fever (MCF), and are collectively referred to as MCF virus (MCFV) group of organisms, diseases and/or clinical syndromes have not been associated with BoGHV6 and porcine lymphotropic herpesvirus (PLHV). This report investigated the occurrence of BoGHV6 in tissues of aborted dairy fetuses known to be infected by Histophilus somni to identify possible disease patterns associated with infection by this Macavirus. A nested-PCR (nPCR) assay was used to amplify the BoGHV6 polymerase gene from multiple tissues of 13 fetuses and the cow of one of these which were derived from seven dairy herds located in three geographical regions of Brazil. Direct sequencing confirmed the results of the nPCR assays. Additionally, all fetal tissues were previously investigated for the presence of H. somni, Listeria monocytogenes, Neospora caninum, Brucella abortus, Leptospira spp., bovine alphaherpesvirus 1, and bovine viral diarrhea virus (BVDV) by PCR and/or RT-PCR assays. The nPCR assay amplified BoGHV6 DNA from fetuses of most dairy herds (85.7%; 6/7) investigated, resulting in the amplification of BoGHV6 from 76.9% (10/13) of all fetuses evaluated from two geographical and important cattle-producing regions of Brazil. Furthermore, only BoGHV6 was identified in the spleen (n = 3), myocardium, and kidney (n = 2) of five fetuses, and BoGHV6 was the only agent associated with myocarditis in one of these. Nevertheless, dual, triple, and quadruple infections (including BVDV, B. abortus, and N. caninum) were identified in fetuses that were concomitantly infected by H. somni. Phylogenetic analysis revealed that the strain herein identified has 100% nucleotide (nt) sequence identity with wild type strains of BoGHV6 circulating in ruminants from Brazil and 99.8% nt identity with the reference strain of BoGHV6 but was 72.2-73.3% and 67.4-68.2% different from members of the MCFV group and PLHV, respectively. These results demonstrated that 76.9% of the fetuses evaluated were infected by BoGHV6, most likely via vertical infection resulting in transplacental transmission. Considering that most fetuses were concomitantly infected by BoGHV6 and H. somni the real impact of this viral infection cannot be efficiently determined. However, since BoGHV6 was the only pathogen identified in the myocardium of one fetus with myocarditis by histopathology, the possible participation of this Macavirus in the etiopathogenesis of the myocardial disease observed in this fetus cannot be ignored or discarded. However, the mere amplification of BoGHV6 DNA from the myocardium is not enough to establish a definite association between cause and effect, since in situ evaluations and experimental studies would be needed to confirm this agent in the etiopathogenesis of fetal diseases and/or abortions in cattle. Consequently, additional studies are needed to determine the exact role, if any, of BoGHV6 in the development of fetal disease, and possibly fetal mortality.

Novel compound heterozygous variants in XYLT1 gene caused Desbuquois dysplasia type 2 in an aborted fetus: a case report.

BACKGROUND: Desbuquois dysplasia type 2 (DBQD2) is an infrequent dysplasia with a wide range of symptoms, including facial deformities, growth retardation and short long bones. It is an autosomal recessive disorder caused by mutations in the XYLT1 gene that encodes xylosyltransferase-1. CASE PRESENTATION: We studied an aborted fetus from Iranian non-consanguineous parents who was therapeutically aborted at 19 weeks of gestation. Ultrasound examinations at 18 weeks of gestation revealed growth retardation in her long bones and some facial problems. Whole-exome sequencing was performed on the aborted fetus which revealed compound heterozygous XYLT1 mutations: c.742G>A; p.(Glu248Lys) and c.1537 C>A; p.(Leu513Met). Sanger sequencing and segregation analysis confirmed the compound heterozygosity of these variants in XYLT1. CONCLUSION: The c.1537 C>A; p.(Leu513Met) variant has not been reported in any databases so far and therefore is novel. This is the third compound heterozygote report in XYLT1 and further supports the high heterogeneity of this disease.

Stepwise molecular-genetic examination in aborted fetuses.

OBJECTIVE: The evaluation of quantitative fluorescence PCR (QF-PCR) and single nucleotide polymorphism array (SNP array) analysis for the identification of chromosomal abnormalities in products of conception (POC). MATERIALS AND METHODS: A total of 1,094 POC samples were processed at Gennet in the years 2018-2020. Chromosomal aneuploidies were tested by QF-PCR using a Omnibor set (STR markers 13, 18, 21, X a Y), SAB-I set (STR markers 2, 7, 15, 16, 22), SAB-II set (from November 2019, STR markers 4, 6, 14) followed by SNP array analysis (Illumina) on samples with a negative QF-PCR result. All POC samples were tested for maternal contamination. RESULTS: After exclusion of maternal contamination (32% samples) the total number of 742 POC samples were tested by QF-PCR. Chromosomal aneuploidies were found in 273 POC samples (36.8%). Then, 469 QF-PCR negative POC samples were tested by SNP array analysis. Normal female/male profile was confirmed in 402 samples (85.7%) and chromosomal aneuploidies and chromosomal aberrations (deletion/duplication > 10 Mb) in 51 samples (10.9%). Microdeletion/microduplication was found in 16 POC samples (3.4%), two were classified as pathogenic variants and 14 as variants of unknown significance. In a group of women > 35 years of age, statistically significant increase of the chromosomal abnormalities was confirmed. No statistically significant difference between the in vitro fertilization group and the group of spontaneous conception was found. CONCLUSION: The application of the molecular work-up based on the stepwise use of QF-PCR and SNP array clarifies the cause of the abortion in 43% POC samples. The overall detection rate in the I. trimester was 50.4%.

Genetic characterization of Toxoplasma gondii isolates from human spontaneous aborted fetuses in Jahrom, southern Iran.

Toxoplasma gondii (T. gondii) is an intracellular protozoan that infects the fetus through the placenta and leads to severe complications in the fetus. One of the complications of congenital toxoplasmosis is spontaneous abortion. The prevalence of toxoplasmosis infection was investigated among spontaneously aborted fetuses (SAFs), and the genotypes of parasite isolates were determined in the present study. Placentas from 330 samples of SAFs were collected in Jahrom (Fars province) from February to September 2018. DNA was extracted from each placental tissue. The T. gondii infection was detected using nested polymerase chain reaction (Nested-PCR) assay based on a 529 bp repeat element (RE) gene. Afterward, Toxoplasma was genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) based on the GRA6 gene. The frequency of T. gondii infection was found to be 14.5% (48 out of 330 samples). Genotyping of nine T. gondii isolates revealed that all belonged to genotype II. Statistically, the prevalence of T. gondii infection was significantly correlated with the education levels of the mothers and the age of the fetus (P < 0.05). The lowest prevalence of Toxoplasma infection belonged to mothers with university education and the highest frequency of infection was observed among the fetuses in the age group of 8-9 weeks. The findings of the present study suggest a significant role for toxoplasmosis in SAFs in Jahrom city.

Lethal Cenani Lenz syndrome in two consecutive pregnancies: Further extension of phenotype from Maldives.

Cenani Lenz syndrome is a rare autosomal recessive disorder associated with variable degree of limb malformations, dysmorphism, and renal agenesis. It is caused due to pathogenic variants in the LRP4 gene, which plays an important role in limb and renal development. Mutations in the APC gene have also been occasionally associated with CLS. The phenotypic spectrum ranges from mild to very severe perinatal lethal type depending on the type of variant. We report a pathogenic variant, c.2710 del T (p.Trp904GlyfsTer5) in theLRP4 gene, in a fetus with lethal Cenani Lenz syndrome with antenatal presentation of tetraphocomelia and symmetrical involvement of hands and feet.

A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

Karyotype of first clinical miscarriage and prognosis of subsequent pregnancy outcome.

RESEARCH QUESTION: Is the karyotype of the first clinical miscarriage in an infertile patient predictive of the outcome of the subsequent pregnancy? DESIGN: Retrospective cohort study of infertile patients undergoing manual vacuum aspiration with chromosome testing at the time of the first (index) clinical miscarriage with a genetic diagnosis and a subsequent pregnancy. Patients treated at two academic-affiliated fertility centres from 1999 to 2018 were included; those using preimplantation genetic testing for aneuploidy were excluded. Main outcome was live birth in the subsequent pregnancy. RESULTS: One hundred patients with euploid clinical miscarriage and 151 patients with aneuploid clinical miscarriage in the index pregnancy were included. Patients with euploid clinical miscarriage in the index pregnancy had a live birth rate of 63% in the subsequent pregnancy compared with 68% among patients with aneuploid clinical miscarriage (adjusted odds ratio [aOR] 0.75, 95% CI 0.47-1.39, P = 0.45, logistic regression model adjusting for age, parity, body mass index and mode of conception). In a multinomial logistic regression model with three outcomes (live birth, clinical miscarriage or biochemical miscarriage), euploid clinical miscarriage for the index pregnancy was associated with similar odds of clinical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage for the index pregnancy (32% versus 24%, respectively, aOR 1.49, 95% CI 0.83-2.70, P = 0.19). Euploid clinical miscarriage for the index pregnancy was not associated with likelihood of biochemical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage (5% versus 8%, respectively, aOR 0.46, 95% CI 0.14-1.55, P = 0.21). CONCLUSION: Prognosis after a first clinical miscarriage among infertile patients is equally favourable among patients with euploid and aneuploid karyotype, and independent of the karyotype of the pregnancy loss.

Genetic Diversity of Porcine Circovirus Subtypes from Aborted Sow Fetuses in Vietnam.

Porcine circovirus type 3 (PCV3) is an emerging circovirus that is highly distributed among swine worldwide and associated with porcine dermatitis and nephropathy syndrome, reproductive failure, and multisystemic inflammation. Here, we investigated and characterized PCV3 from aborted fetuses in Vietnam. We found that the whole genomes of PCV3 collected in these Vietnamese pig farms share 98.4-99.45% sequence identity with reference PCV3 sequences. Several distinct mutation were identified in both the Rep protein and Cap protein of these strains. These strains were clustered into two distinct subtypes (3a1 and 3b). This study contributes to a better understanding of the molecular characteristics and genetic diversity of PCV3 in Vietnam.

Anatomical variations of the tibialis anterior tendon.

INTRODUCTION: The tibialis anterior muscle originates from the medial part of the anterior compartment, from the upper two-thirds of the lateral surface of the tibia and the adjacent part of the interosseous membrane, and typically inserts to the medial cuneiform and first metatarsal bone. The goal of the study was to examine the insertion of the tibialis anterior tendon and create a classification in human fetuses. MATERIALS AND METHODS: Fifty spontaneously-aborted human fetuses (26 male, 24 female, 100 lower limbs), aged 18-38 weeks of gestation at death were examined. RESULTS: The classification comprised five types of tibialis anterior tendon insertion. The most common was Type V (60%), which was characterized by a single tendon inserting onto the medial cuneiform bone. The second most frequent was Type I (19%), which was characterized by a tendon which split into two equal-sized parts that insert to the medial cuneiform bone and the base of the first metatarsal. The third was Type II (12%), which was characterized by a tendon splitting into two different-sized parts that inserted onto the medial cuneiform bone (larger component) and the base of the first metatarsal (smaller component). The fourth type was Type III (5%), which was also characterized by a tendon splitting into two different-sized parts that inserted onto the medial cuneiform bone (smaller component) and the base of the first metatarsal (larger component). Finally, Type VI (4%), the least frequent type, was characterized by a tendon splitting into three different-sized parts, inserting onto the medial cuneiform bone (the smallest component) and the base of the first metatarsal (the middle and larger component). CONCLUSION: The tibialis anterior muscle is characterized by high variability in the approach of its tendon to the foot, at least in fetuses. This is classified in the present study for the first time.

The twisted structure of the fetal calcaneal tendon is already visible in the second trimester.

INTRODUCTION: The progress in morphological science results from the greater possibilities of intra-pubic diagnosis and treatment of congenital disabilities, including the motor system. However, the structure and macroscopic development of the calcaneal tendon have not been investigated in detail. Studies on the adult calcaneal tendon showed that the calcaneal tendon is composed of twisted subtendons. This study aimed to investigate the internal structure of the fetal calcaneal tendon in the second trimester. MATERIALS AND METHODS: Thirty-six fetuses fixed in 10% formaldehyde were dissected using the layer-by-layer method and a surgical microscope. RESULTS: The twisted structure of the calcaneal tendon was revealed in all specimens. The posterior layer of the calcaneal tendon is formed by the subtendon from the medial head of the gastrocnemius muscle. In contrast, the anterior layer is formed by the subtendon from the lateral head of the gastrocnemius muscle. The subtendon from the soleus muscle constitutes the anteromedial outline of the calcaneal tendon. The lateral outline of the calcaneal tendon is formed by the subtendon originating from the medial head of the gastrocnemius muscle. In contrast, the medial outline is formed by the subtendon from the soleus muscle. In most of the examined limbs, the plantaris tendon attached to the tuber calcanei was not directly connected to the calcaneal tendon. CONCLUSIONS: The twisted structure of the subtendons of the fetal calcaneal tendon is already visible in the second trimester and is similar to that seen in adults.

Prenatal development of the human tympanic ring: a morphometric study with clinical correlations.

PURPOSE: To establish normal reference values for the human Tympanic Ring (TR) during prenatal development, and to describe and interpret its growth dynamics. METHODS: Fifty spontaneously aborted human fetuses aged 12-37 weeks with normal external characteristics were evaluated. The parameters measured in the TR were the cephalocaudal and dorsoventral axes, total area, thickness, height, and length and angle of the notch of Rivinus (NR). Data were subjected to statistical analysis. RESULTS: The following values were obtained at the end of fetal development: cephalocaudal and dorsoventral axes, 10.03 and 8.3 mm, respectively; ratio between the two axes, 120%; total area, 65.63 mm2; height and thickness, 0.88 mm and 1.10 mm, respectively; and length and angle of the NR, 4.66 mm and 26.2 degrees, respectively. There were variations in the length of the dorsoventral axis throughout fetal development that affected all other parameters, except for the cephalocaudal axis. There were no sex-based differences in TR size. CONCLUSION: The prenatal development of the TR is dynamic as evidenced by the size variations noted throughout fetal development. Notwithstanding, this structure is a reliable and sensitive marker of developmental abnormalities of the external and middle ear.

Ellis-van Creveld syndrome: Report of a case and recurrent variant.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is a rare autosomal recessive skeletal dysplasia that is characterized by short stature, short limbs, short ribs, polydactyly and structural heart defect. Despite locus heterogeneity, in the majority of the cases, the disorder segregates with mutations in the EVC and EVC2 genes, notably mutations with truncating protein as a final sequence. In the present study, we report the prenatal findings and genetic analysis of a terminated pregnancy affected by severe thoracic and skeletal dysplasia. METHODS: After detailed physical and clinical examination, whole exome sequencing (WES) was performed and the variant was confirmed by Sanger sequencing. RESULTS: One homozygote variant in EVC2 gene was identified in the fetus (NM_147127, c.942G>A, p.W314X). The EVC2 gene is strongly associated with EvCS, which is consistent with the sonographic findings of the fetus. CONCLUSIONS: The homozygous p.W314X mutation found in this family was recently reported to be segregated in a consanguineous family originating from Pakistan. The occurrence of the p.W314X mutation in two unrelated families (Iranian and Pakistani) may be the result of an old founder effect or arose because of a mutational hotspot and is supporting evidence for the pathogenicity of this variant. Because skeletal dysplasia belongs to a broad spectrum of syndromes and therefore exhibits considerable background locus and allelic heterogeneity, our report highlights the need for appropriate genetic counseling and supports the feasibility of WES to determine an accurate diagnosis, as well as precise recurrence risk prediction.

Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype.

INTRODUCTION: Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging. CASE REPORT: A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5. METHODS: Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls. RESULTS: ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype. CONCLUSION: This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

ALG3-CDG: lethal phenotype and novel variants in Chinese siblings.

Congenital disorders of glycosylation (CDG) are a group of genetic, mostly multisystem disorders, which often involve the central nervous system. ALG3-CDG is one the some 130 known CDG. Here we report two siblings with a severe phenotype and intrauterine death. Whole-exome sequencing revealed two novel variants in ALG3: NM_005787.6:c.512G>T (p.Arg171Leu) inherited from the mother and NM_005787.6:c.511C>T (p.Arg171Trp) inherited from the father.

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.