{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:46:22Z","timestamp":1791812782014,"version":"4.3.4"},"reference-count":13,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"Suppl 3","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Genetic disorders presenting during the prenatal period are often complex, with overlapping phenotypes that pose significant diagnostic challenges. The increasing use of advanced fetal imaging modalities such as targeted imaging for fetal anomalies and high-resolution ultrasonography has enabled early identification of structural anomalies suggestive of syndromic conditions. However, correlating radiological findings with underlying genetic alterations remains difficult, particularly when variants of uncertain significance (VUSs) are detected. A VUS classification means that there is insufficient or conflicting evidence regarding a molecular alteration\u2019s role in disease. VUSs are categorized by the American College of Medical Genetics and Genomics within a five-tier system that also includes pathogenic, likely pathogenic, likely benign, and benign variants. The clinical interpretation of VUS is a recognized limitation in prenatal genetics, as these variants lack sufficient evidence for definitive pathogenic or benign classification, yet may contribute to phenotypic variability. Disorders such as Marfan syndrome (MFS), acromicric dysplasia (ACMICD), and coloboma, heart defects, ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME) syndrome are genetically heterogeneous and share overlapping clinical features, complicating precise delineation. Furthermore, the absence of parental genotyping often restricts the assessment of\n                    <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                    variants and allelic segregation. In such scenarios, integrating fetal imaging, genomic sequencing, and functional predictive scores becomes essential to guide counseling and management. Reporting novel and blended phenotypes with VUS contributes to the growing body of evidence, facilitating refinement of variant classification and aiding clinical decision-making in subsequent pregnancies. We hereby report a case of fetus purporting as a blended phenotype with multiple skeletal and cardiac defects that harbors a heterozygous VUS in the\n                    <jats:italic toggle=\"yes\">FBN1<\/jats:italic>\n                    gene and a novel, homozygous VUS in the\n                    <jats:italic toggle=\"yes\">PIGL<\/jats:italic>\n                    gene. The index patient is a spontaneously aborted 21-week-old fetus of a nonconsanguineously married couple. Grossly, it had retrognathia, low-set ears, cleft palate, depressed nasal bridge, and short neck. Targeted anomaly scan at 20 weeks of gestation showed the possibility of short-limb dwarfism, skeletal dysplasia with narrow thorax likely to be lethal, short and broad neck, congenital cardiac anomaly (tetralogy of Fallot with pulmonary stenosis), bilateral gross hydronephrosis and hydroureter, absent nasal bone, flat midface, micrognathia, and low-set ears, dilated cisterna magna, vermian agenesis, and Blake\u2019s pouch cyst. The fetal whole-genome sequence was found to harbor an autosomal dominant, heterozygous VUS in the\n                    <jats:italic toggle=\"yes\">FBN1<\/jats:italic>\n                    gene at exon 18 associated with MFS and ACMICD. It also had an autosomal recessive homozygous VUS, possibly a mutational \u201chot spot\u201d in the\n                    <jats:italic toggle=\"yes\">PIGL<\/jats:italic>\n                    gene at exon 1 associated with CHIME syndrome.\n                    <jats:italic toggle=\"yes\">De novo<\/jats:italic>\n                    status of the variants cannot be ascertained, as parental genotyping could not be performed. Postgenetic test counseling was performed for the couple and was informed of the chances of affection with the same in subsequent offsprings. Based on VUS, important clinical management decisions or prenatal diagnosis are not recommended unless strongly correlated with the phenotype. CHIME syndrome is known to be expressed in homozygosity, while the autosomally dominant\n                    <jats:italic toggle=\"yes\">FBN1<\/jats:italic>\n                    gene mutation can manifest in heterozygosity. The presence of VUS variants in this case provides a genotype\u2013phenotypic correlation to say that the variants might be the disease-causing ones. In the absence of a parental genomic study, the chance of co-inheritance of the variants in successive pregnancies ranges from 25% to 100%. Prenatal testing options in future pregnancies may be considered.\n                  <\/jats:p>","DOI":"10.4103\/aam.aam_306_26","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:46:14Z","timestamp":1782848774000},"page":"S654-S659","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Blended Phenotype Involving FBN1 and Novel PIGL Variants of Uncertain Significance: A Prenatal Case Report"],"prefix":"10.4103","volume":"25","author":[{"given":"Mitul","family":"Suhane","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrashekhar","family":"Shrivastava","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinita","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"R2-20261012","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1016\/j.gim.2022.03.013","article-title":"The clinical variant analysis tool: Analyzing the evidence supporting reported genomic variation in clinical practice","volume":"24","author":"Chin","year":"2022","journal-title":"Genet Med"},{"key":"R3-20261012","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"key":"R6-20261012","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/ajmg.1320150217","article-title":"New syndrome of congenital ichthyosis with neurologic abnormalities","volume":"15","author":"Zunich","year":"1983","journal-title":"Am J Med Genet"},{"key":"R7-20261012","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1136\/jmg.32.6.465","article-title":"Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases","volume":"32","author":"Shashi","year":"1995","journal-title":"J Med Genet"},{"key":"R8-20261012","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ajhg.2012.02.010","article-title":"Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome","volume":"90","author":"Ng","year":"2012","journal-title":"Am J Hum Genet"},{"key":"R9-20261012","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/j.1525-1470.1996.tb00702.x","article-title":"Zunich neuroectodermal syndrome: migratory ichthyosiform dermatosis, colobomas, and other abnormalities","volume":"13","author":"Tinschert","year":"1996","journal-title":"Pediatr Dermatol"},{"key":"R10-20261012","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/(SICI)1096-8628(19971003)72:1<24::AID-AJMG5>3.0.CO;2-V","article-title":"Acute lymphoblastic leukemia in a child with the CHIME neuroectodermal dysplasia syndrome","volume":"72","author":"Schnur","year":"1997","journal-title":"Am J Med Genet"},{"key":"R11-20261012","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1046\/j.1525-1470.2001.018003252.x","article-title":"What syndrome is this? CHIME syndrome","volume":"18","author":"Sidbury","year":"2001","journal-title":"Pediatr Dermatol"},{"key":"R12-20261012","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/ajmg.a.38181","article-title":"Alu-mediated deletion of PIGL in a Patient with CHIME syndrome","volume":"173","author":"Knight Johnson","year":"2017","journal-title":"Am J Med Genet A"},{"key":"R13-20261012","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1590\/1678-4685-gmb-2017-0172","article-title":"Large deletion in PIGL: A common mutational mechanism in CHIME syndrome?","volume":"41","author":"Ceroni","year":"2018","journal-title":"Genet Mol Biol"},{"key":"R14-20261012","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/pde.14969","article-title":"Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report","volume":"39","author":"Rolland","year":"2022","journal-title":"Pediatr Dermatol"},{"key":"R15-20261012","doi-asserted-by":"crossref","first-page":"e63962","DOI":"10.1002\/ajmg.a.63962","article-title":"CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant","volume":"197","author":"Arany","year":"2024","journal-title":"Am J Med Genet"},{"issue":"(4)","key":"R16-20261012","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ajhg.2012.02.010","article-title":"Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome","volume":"90","author":"Ng","year":"2012","journal-title":"Am J Hum Genet"}],"container-title":["Annals of African Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/aam.aam_306_26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:01:57Z","timestamp":1791810117000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/aam.aam_306_26"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":13,"journal-issue":{"issue":"Suppl 3","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/aam.aam_306_26","relation":{},"ISSN":["1596-3519","0975-5764"],"issn-type":[{"value":"1596-3519","type":"print"},{"value":"0975-5764","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]},"assertion":[{"value":"2026-03-19","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-08","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}