Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

Chorioangioma: a single tertiary care center retrospective study.

OBJECTIVES: Chorioangioma represents a challenge due to the rarity of the condition, paucity of sufficient management guidelines, and controversies regarding the best invasive fetal therapy option; most of the scientific evidence for clinical treatment has been limited to case reports. The aim of this retrospective study was to review the natural antenatal history, maternal and fetal complications, and therapeutic modalities used in pregnancies complicated with placental chorioangioma at a single Center. METHODS: This retrospective study was conducted at King Faisal Specialist Hospital and Research Center (KFSH&RC) in Riyadh, Saudi Arabia. Our study population included all pregnancies with ultrasound features of chorioangioma, or histologically confirmed chorioangiomas, between January 2010 and December 2019. Data were collected from the patients' medical records, including the ultrasound reports and histopathology results. All subjects were kept anonymous; case numbers were used as identifiers. Data collected by the investigators were entered into Excel worksheets in an encrypted format. A MEDLINE database was used to retrieve 32 articles for literature review. RESULTS: Over a 10-year period between January 2010 and December 2019, 11 cases of chorioangioma were identified. Ultrasound remains the gold standard for diagnosis and follow-up of the pregnancy. Seven of the 11 cases were detected by ultrasound, allowing proper fetal surveillance and antenatal follow-up. Of the remaining six patients, one underwent radiofrequency ablation, two underwent intrauterine transfusion for fetal anemia due to placenta chorioangioma, one had vascular embolization with an adhesive material, and two were managed conservatively until term with ultrasound surveillance. CONCLUSIONS: Ultrasound remains the gold standard modality for prenatal diagnosis and follow-up of pregnancies with suspected chorioangiomas. Tumor size and vascularity play a significant role in the development of maternal-fetal complications and the success of fetal interventions. To determine the superior modality of fetal intervention mandates more data and research; nevertheless, Fetoscopic Laser Photocoagulation and embolization with adhesive material seem to be a lead choice, with reasonable fetal survival.

Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes.

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder.

PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Potential health risks of maternal phthalate exposure during the first trimester - The Saudi Early Autism and Environment Study (SEAES).

Phthalates are the most ubiquitous contaminants that we are exposed to daily due to their wide use as plasticizers in various consumer products. A few studies have suggested that in utero exposure to phthalates can disturb fetal growth and development in humans, because phthalates can interfere with endocrine function. We collected spot urine samples from 291 pregnant women in their first trimester (9.8 ± 2.3 gestational weeks) recruited in an ongoing prospective cohort study in Saudi Arabia. A second urine sample was collected within 1-7 d after enrollment. The aims of this study were to: (1) assess the extent of exposure to phthalates during the first trimester and (2) estimate the risk from single and cumulative exposures to phthalates. Most phthalate metabolites' urinary levels were high, several-fold higher than those reported in relevant studies from other countries. The highest median levels of monoethyl phthalate, mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), and mono-(2-ethylhexyl) phthalate (MEHP) in µg/l (µg/g creatinine) were 245.62 (197.23), 114.26 (99.45), 39.59 (34.02), and 23.51 (19.92), respectively. The MEHP levels were highest among three di (2-ethylhexyl) phthalate (DEHP) metabolites. %MEHP4, the ratio of MEHP to four di (2-ethylhexyl) phthalate metabolites (∑4DEHP), was 44%, indicating interindividual differences in metabolism and excretion. The hazard quotient (HQ) of individual phthalates estimated based on the reference dose (RfD) of the U.S. Environmental Protection Agency indicated that 58% (volume-based) and 37% (creatinine-based) of the women were at risk of exposure to ∑4DEHP (HQ > 1). Based on the tolerable daily intake (TDI) from the European Food Safety Authority, 35/12% (volume-/creatinine-based data) of the women were at risk of exposure to two dibutyl phthalate (∑DBP) metabolites (MiBP and MnBP). The cumulative risk was assessed using the hazard index (HI), the sum of HQs of all phthalates. The percentages of women (volume-/creatinine-based data) at health risks with an HI > 1 were 64/40% and 42/22% based on RfD and TDI, respectively. In view of these indices for assessing risk, our results for the anti-androgenic effects of exposing pregnant women to ∑4DEHP and ∑DBP early during pregnancy are alarming.

Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families.

BACKGROUND: Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. METHODS: Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. RESULTS: In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. CONCLUSIONS: Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.

Molecular autopsy in maternal-fetal medicine.

PurposeThe application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.MethodsIn this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing.ResultsPathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality (ALPL, GUSB, SLC17A5, MRPS16, THSD1, PIEZO1, and CTSA), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality (INVS, FKTN, MYBPC3, COL11A2, KRIT1, ASCC1, NEB, LZTR1, TTC21B, AGT, KLHL41, GFPT1, and WDR81) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence (MS4A7, SERPINA11, FCRL4, MYBPHL, PRPF19, VPS13D, KIAA1109, MOCS3, SVOPL, FEN1, HSPB11, KIF19, and EXOC3L2).ConclusionOur results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

Identification of a novel MKS locus defined by TMEM107 mutation.

Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel.

BACKGROUND: Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease. METHODS: To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated. RESULTS: In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort. CONCLUSIONS: In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.

PURPOSE: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. METHODS: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. RESULTS: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. CONCLUSION: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.

Assessment of maternal phthalate exposure in urine across three trimesters and at delivery (umbilical cord blood and placenta) and its influence on birth anthropometric measures.

Phthalates, commonly used in plastic manufacturing, have been linked to adverse reproductive effects. Our research from the Saudi Early Autism and Environment Study (2019-2022), involving 672 participants, focused on the impacts of maternal phthalate exposure on birth anthropometric measures. We measured urinary phthalate metabolites in 390 maternal samples collected during each of the three trimesters of pregnancy and in cord serum and placental samples obtained at delivery. We employed various statistical methods to analyze our data. Intraclass correlation coefficients were used to assess the consistency of phthalate measurements, generalized estimating equations were used to explore temporal variations across the trimesters, and linear regression models, adjusted for significant confounders and Bonferroni correction, were used for each birth outcome. Exposure to six phthalates was consistently high across trimesters, with 82 %-100 % of samples containing significant levels of all metabolites, except for mono-benzyl phthalate. We found a 3.15 %-3.73 % reduction in birth weight (BWT), 1.39 %-1.69 % reduction in head circumference (HC), and 3.63 %-5.45 % reduction in placental weight (PWT) associated with a one-unit increase in certain urinary di(2-ethylhexyl) phthalate (DEHP) metabolites during the first trimester. In the second trimester, exposure to MEP, ∑7PAE, and ∑LMW correlated with a 3.15 %-4.5 % increase in the APGAR 5-min score and increases in PWT by 8.98 % for ∑7PAE and 9.09 % for ∑LMW. Our study also highlighted the maternal-to-fetal transfer of DEHP metabolites, indicating diverse impacts on birth outcomes and potential effects on developmental processes. Our study further confirmed the transfer of DEHP metabolites from mothers to fetuses, evidenced by variable rates in the placenta and cord serum, with an inverse relationship suggesting a passive transfer mechanism. Additionally, we observed distinct phthalate profiles across these matrices, adversely impacting birth outcomes. In serum, we noticed increases associated with DEHP metabolites, with birth gestational age rising by 1.01 % to 1.11 %, HC by 2.84 % to 3.67 %, and APGAR 5-min scores by 3.77 % to 3.87 %. Conversely, placental analysis revealed a different impact: BWT decreased by 3.54 % to 4.69 %, HC reductions ranged from 2.57 % to 4.69 %, and chest circumference decreased by 7.13 %. However, the cephalization index increased by 3.67 %-5.87 %. These results highlight the complex effects of phthalates on fetal development, indicating their potential influence on crucial developmental processes like sexual maturation and brain development.

Phthalate exposure during pregnancy and its association with thyroid hormones: A prospective cohort study.

Phthalate esters (PAEs) possess endocrine-disrupting properties. Studies in humans have indicated that in utero phthalate exposure affects maternal thyroid hormones, which are essential for fetal growth and development. However, these studies also reported inconsistent results on the relationship between phthalates and thyroid hormones. This prospective cohort study aimed to assess phthalate exposure across the three trimesters of pregnancy and its association with thyroid hormone levels. From 2019 to 2022, we recruited 672 pregnant women, and two urine samples and one blood sample were collected from each participant during the pregnancy. We examined the urine samples from 663, 335, and 294 women in the first, second, and third trimester, respectively, for the following seven phthalate metabolites: monoethyl phthalate (MEP) from diethyl phthalate (DEP); mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP) from dibutyl phthalate (DBP); monobenzyl phthalate (MBzP) from butyl benzyl phthalate; and three di(2-ethylhexyl) phthalate (DEHP) metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Additionally, we examined the levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH), and total triiodothyronine (TT3) in the serum samples of the following participants: 596, 627, and 576 in the first trimester; 292, 293, and 282 in the second trimester; and 250, 250, and 248 in the third trimester, respectively. Other than MBzP, which was detected in 25%-33% of the samples, other metabolites were detectable in >86% of urine samples, indicating widespread exposure to DEP, DBP, and DEHP. The detected phthalate exposure levels in our cohort were significantly higher than those reported in other countries. Metabolite levels varied across the trimesters, implying changes in exposure and metabolism throughout pregnancy. The observed variability in urinary concentrations of phthalate metabolites, which ranged from poor to moderate, underscores the importance of taking multiple measurements during pregnancy for precise exposure assessment. Using a linear mixed model, we analyzed the effects of repeated phthalate exposure on thyroid hormone levels while adjusting for potential confounders. We observed significant linear trends in FT4, TSH, and, to a lesser extent, TT3 across quartiles of specific phthalate metabolites. Comparing the highest to the lowest quartiles, we found a significant increase in FT4 levels, ranging from 2 to 3.7%, associated with MEP; MECPP; MEHHP; and the sum of seven metabolites (∑7PAE), three DEHP metabolites (∑3DEHP), two DBP metabolites (∑DBP), and both low molecular weight (∑LMW) and high molecular weight metabolites. Increased TSH levels (5%-16%) were observed for all phthalate metabolites (except MEHHP) and their molar sums, including ∑7PAE. For TT3, a significant increase was observed with MEP (2.2%) and a decrease was observed with ∑DBP (-2.7%). A higher TSH/FT4 ratio was observed with the highest quartiles (third or fourth) of several phthalate metabolites: MEP (8.8%), MiBP (8.7%), MnBP (22.2%), ∑7PAE (15.3%), ∑DBP (16.4%), and ∑LMW (18.6%). These hormonal alterations, most notably in the second and third trimesters, suggest that phthalate exposure may impact fetal growth and development by affecting maternal thyroid function.

Observational cohort study of perinatal outcomes of women with COVID-19.

BACKGROUND: Understanding the impact of SARS-CoV-2 infection on pregnancy outcomes and of pregnancy on COVID-19 outcomes is critical for ensuring proper prenatal and antenatal care. No similar studies have been published in Saudi Arabia. METHODS: We performed a prospective cohort study of pregnant women with confirmed SARS-CoV-2 infection who presented at King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Kingdom of Saudi Arabia. COVID-19 staging was performed, pregnancy-related complications were assessed, and neonatal infection was evaluated. RESULTS: We enrolled 81 patients (mean age 31.75 years, SD 5.25) of which there were 17 cases in the first trimester, 20 in the second trimester, and 34 in the third trimester. The distribution of COVID-19 severity was 40 patients with Stage A, 36 with Stage B, 4 with Stage C, and 1 with Stage D. Complications were pregnancy loss in 2 patients (one in each first and second trimester) and 1 fetal death after 20 weeks of pregnancy, 7 patients with fetal growth restriction, and 8 with pre-term delivery. CONCLUSIONS: We did not observe an unusual frequency of pregnancy-related complications due to SARS-CoV-2 infection in this high-risk obstetric population and there was no evidence of vertical transmission in newborns from women who delivered while positive for the virus.

Characterizing the morbid genome of ciliopathies.

BACKGROUND: Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. RESULTS: We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their "mutation load" beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. CONCLUSIONS: Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.