@article {983, title = {Perturbations of genes essential for M{\"u}llerian duct and W{\"o}lffian duct development in Mayer-Rokitansky-K{\"u}ster-Hauser syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {337-345}, abstract = {

Mayer-Rokitansky-K{\"u}ster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the M{\"u}llerian ducts (MD)/W{\"o}lffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

}, keywords = {46, XX Disorders of Sex Development, Adult, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 7, Codon, Nonsense, Congenital Abnormalities, Female, Genetic Association Studies, Genetic Pleiotropy, Homeobox A10 Proteins, Homeodomain Proteins, Humans, Mullerian Ducts, Mutation, Paternal Inheritance, PAX8 Transcription Factor, Penetrance, T-Box Domain Proteins, Transcription Factors, Wnt Proteins, Wolffian Ducts}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.12.014}, author = {Chen, Na and Zhao, Sen and Jolly, Angad and Wang, Lianlei and Pan, Hongxin and Yuan, Jian and Chen, Shaoke and Koch, Andr{\'e} and Ma, Congcong and Tian, Weijie and Jia, Ziqi and Kang, Jia and Zhao, Lina and Qin, Chenglu and Fan, Xin and Rall, Katharina and Coban-Akdemir, Zeynep and Chen, Zefu and Jhangiani, Shalini and Liang, Ze and Niu, Yuchen and Li, Xiaoxin and Yan, Zihui and Wu, Yong and Dong, Shuangshuang and Song, Chengcheng and Qiu, Guixing and Zhang, Shuyang and Liu, Pengfei and Posey, Jennifer E and Zhang, Feng and Luo, Guangnan and Wu, Zhihong and Su, Jianzhong and Zhang, Jianguo and Chen, Eugenia Y and Rouskas, Konstantinos and Glentis, Stavros and Bacopoulou, Flora and Deligeoroglou, Efthymios and Chrousos, George and Lyonnet, Stanislas and Polak, Michel and Rosenberg, Carla and Dingeldein, Irene and Bonilla, Ximena and Borel, Christelle and Gibbs, Richard A and Dietrich, Jennifer E and Dimas, Antigone S and Antonarakis, Stylianos E and Brucker, Sara Y and Lupski, James R and Wu, Nan and Zhu, Lan} } @article {909, title = {Deciphering congenital anomalies for the next generation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 10}, abstract = {

Congenital anomalies are common, with 2\%-3\% of infants estimated to have at least one major congenital malformation and countless others with minor malformations of lesser cosmetic or medical importance. As congenital malformations are major drivers of morbidity and mortality, representing the leading cause of infant mortality in the United States, there is substantial interest in understanding the underlying etiologies-particularly if modifiable causes may be identified or pre- or postnatal treatments can be offered. Recent research has begun to reveal the spectrum of monogenic disorders that commonly result in birth defects, and newer approaches have revealed non-Mendelian genetic contributions including gene-environment interactions. Our experience suggests that increased efforts to sequence and analyze cases of perinatal death, as well as continued global collaboration, will be essential in understanding the genomic landscape of structural anomalies.

}, keywords = {Congenital Abnormalities, Family Characteristics, Female, Humans, Infant, Pregnancy}, issn = {2373-2873}, doi = {10.1101/mcs.a005504}, author = {Wojcik, Monica H and Agrawal, Pankaj B} } @article {751, title = {Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 05}, pages = {1273-1277}, abstract = {

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10\%) and sperm (20\%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

}, keywords = {Congenital Abnormalities, Exome, Fathers, Female, Gene Frequency, Humans, Infant, Newborn, Kidney, Male, Mosaicism, Mutation, Perinatal Death, Pre-B-Cell Leukemia Transcription Factor 1, Pregnancy, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61541}, author = {Arts, Peer and Garland, Jessica and Byrne, Alicia B and Hardy, Tristan S E and Babic, Milena and Feng, Jinghua and Wang, Paul and Ha, Thuong and King-Smith, Sarah L and Schreiber, Andreas W and Crawford, April and Manton, Nick and Moore, Lynette and Barnett, Christopher P and Scott, Hamish S} } @article {703, title = {COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Oct}, pages = {1105-1115}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45\%) that manifests before 30~years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4\% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

}, keywords = {Alleles, Amino Acid Substitution, Collagen Type IV, Computational Biology, Congenital Abnormalities, Databases, Genetic, DNA Mutational Analysis, Evolution, Molecular, Female, Genetic Association Studies, Genetic Loci, Genomics, Heterozygote, Humans, Kidney, Kidney Diseases, Cystic, Male, Mutation, Nephrotic Syndrome, Phenotype, Urinary Tract, Web Browser, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-02042-4}, author = {Kitzler, Thomas M and Schneider, Ronen and Kohl, Stefan and Kolvenbach, Caroline M and Connaughton, Dervla M and Dai, Rufeng and Mann, Nina and Nakayama, Makiko and Majmundar, Amar J and Wu, Chen-Han W and Kari, Jameela A and El Desoky, Sherif M and Senguttuvan, Prabha and Bogdanovic, Radovan and Staji{\'c}, Natasa and Valivullah, Zaheer and Lek, Monkol and Mane, Shrikant and Lifton, Richard P and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {570, title = {TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.}, journal = {Hum Mol Genet}, volume = {28}, year = {2019}, month = {2019 02 15}, pages = {539-547}, abstract = {

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50\%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3\%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

}, keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Congenital Abnormalities, CRISPR-Cas Systems, Disease Models, Animal, Female, Haploinsufficiency, Humans, Infant, Male, Mice, Mutation, Phenotype, Scoliosis, Spine, T-Box Domain Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddy358}, author = {Yang, Nan and Wu, Nan and Zhang, Ling and Zhao, Yanxue and Liu, Jiaqi and Liang, Xiangyu and Ren, Xiaojun and Li, Weiyu and Chen, Weisheng and Dong, Shuangshuang and Zhao, Sen and Lin, Jiachen and Xiang, Hang and Xue, Huadan and Chen, Lu and Sun, Hao and Zhang, Jianguo and Shi, Jiangang and Zhang, Shuyang and Lu, Daru and Wu, Xiaohui and Jin, Li and Ding, Jiandong and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {526, title = {The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {553-567}, abstract = {

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be {\textquoteright}induced{\textquoteright} by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10\%) and pathogenic/likely pathogenic CNVs (overlap 99.69\%) was significantly higher than the random distribution (p < 1 {\texttimes} 10 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

}, keywords = {Adolescent, Congenital Abnormalities, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, Humans, Phenotype, Polymorphism, Single Nucleotide, Scoliosis}, issn = {1432-1203}, doi = {10.1007/s00439-018-1910-3}, author = {Liu, Jiaqi and Zhou, Yangzhong and Liu, Sen and Song, Xiaofei and Yang, Xin-Zhuang and Fan, Yanhui and Chen, Weisheng and Akdemir, Zeynep Coban and Yan, Zihui and Zuo, Yuzhi and Du, Renqian and Liu, Zhenlei and Yuan, Bo and Zhao, Sen and Liu, Gang and Chen, Yixin and Zhao, Yanxue and Lin, Mao and Zhu, Qiankun and Niu, Yuchen and Liu, Pengfei and Ikegawa, Shiro and Song, You-Qiang and Posey, Jennifer E and Qiu, Guixing and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {371, title = {Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.}, journal = {Mitochondrion}, volume = {34}, year = {2017}, month = {2017 05}, pages = {84-90}, abstract = {

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

}, keywords = {Child, Child, Preschool, Congenital Abnormalities, Gene Expression, Humans, Infant, Infant, Newborn, Male, Mitochondrial Proteins, Oxidative Phosphorylation, Peptide Elongation Factor G, RNA Splice Sites}, issn = {1872-8278}, doi = {10.1016/j.mito.2017.02.004}, author = {Simon, Mariella T and Ng, Bobby G and Friederich, Marisa W and Wang, Raymond Y and Boyer, Monica and Kircher, Martin and Collard, Renata and Buckingham, Kati J and Chang, Richard and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Van Hove, Johan L K and Freeze, Hudson H and Abdenur, Jose E} } @article {423, title = {Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {789-802}, abstract = {

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0~{\texttimes} 10 for novel LOF, increased to p = 4.1~{\texttimes} 10 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3~{\texttimes} 10). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

}, keywords = {Alleles, Animals, Case-Control Studies, Clustered Regularly Interspaced Short Palindromic Repeats, Congenital Abnormalities, Exome, Female, Genetic Heterogeneity, Genome-Wide Association Study, Genotype, Heredity, Homozygote, Humans, Kidney, Kidney Diseases, Male, Membrane Proteins, Mice, Mutation, Neoplasm Proteins, Phenotype, RNA, Long Noncoding, Urinary Tract, Urogenital Abnormalities, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.018}, author = {Sanna-Cherchi, Simone and Khan, Kamal and Westland, Rik and Krithivasan, Priya and Fievet, Lorraine and Rasouly, Hila Milo and Ionita-Laza, Iuliana and Capone, Valentina P and Fasel, David A and Kiryluk, Krzysztof and Kamalakaran, Sitharthan and Bodria, Monica and Otto, Edgar A and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Vukojevic, Katarina and Pediaditakis, Igor and Makar, Gabriel S and Mitrotti, Adele and Verbitsky, Miguel and Martino, Jeremiah and Liu, Qingxue and Na, Young-Ji and Goj, Vinicio and Ardissino, Gianluigi and Gigante, Maddalena and Gesualdo, Loreto and Janezcko, Magdalena and Zaniew, Marcin and Mendelsohn, Cathy Lee and Shril, Shirlee and Hildebrandt, Friedhelm and van Wijk, Joanna A E and Arapovic, Adela and Saraga, Marijan and Allegri, Landino and Izzi, Claudia and Scolari, Francesco and Tasic, Velibor and Ghiggeri, Gian Marco and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Mane, Shrikant and Goldstein, David B and Lifton, Richard P and Katsanis, Nicholas and Davis, Erica E and Gharavi, Ali G} } @article {292, title = {Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 Feb}, pages = {67-72}, abstract = {

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5{\textquoteright} splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.

}, keywords = {Abnormalities, Multiple, Congenital Abnormalities, Diabetes Mellitus, Type 1, Digestive System Abnormalities, DNA-Binding Proteins, Duodenal Obstruction, Fatal Outcome, Gallbladder, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Intestinal Atresia, Intestinal Volvulus, Male, Pancreas, Pancreatic Diseases, Regulatory Factor X Transcription Factors, Transcription Factors}, issn = {1399-5448}, doi = {10.1111/pedi.12063}, author = {Concepcion, Jennifer P and Reh, Christina S and Daniels, Mark and Liu, Xiaoming and Paz, Veronica P and Ye, Honggang and Highland, Heather M and Hanis, Craig L and Greeley, Siri Atma W} }