Aug 2026· Intractable & Rare Diseases Research· Vol 15 3, pp.
260-267
· 0 citations
Medicine
TL;DR
The first prenatal case from a non-consanguineous Chinese family presenting with isolated right pelvicalyceal and ureteral dilation at 24 weeks of gestation is reported, highlighting the utility of prenatal exome sequencing in atypical cases and contributing to the understanding of the expanding genetic and phenotypic landscape of ciliopathies.
Abstract
Biallelic variants in a family with sequence similarity 149 member B1 gene (FAM149B1, OMIM #618413) causes a range of abnormal phenotypes associated with Joubert syndrome (JS) in humans. However, the phenotypic spectrum and genetic evidence linking FAM149B1 to ciliopathies remain limited, with no prenatal cases previously described. Here, we report the first prenatal case from a non-consanguineous Chinese family presenting with isolated right pelvicalyceal and ureteral dilation at 24 weeks of gestation. Notably, the fetus lacked cerebellar malformations or hallmark neuroimaging features such as molar tooth sign (MTS). Trio-whole-exome sequencing (Trio-WES) identified novel compound heterozygous loss-of-function variants in FAM149B1: paternal c.279T>A (p.Tyr93*) and maternal c.574dup (p.Ser192Phefs*7). Both variants are predicted to trigger nonsense-mediated mRNA decay (NMD), consistent with a loss-of-function mechanism, and parental segregation confirmed asymptomatic heterozygous carrier status, supporting autosomal recessive inheritance. Gene-disease validity assessment assigned a "Strong" classification to FAM149B1-related ciliopathy under ClinGen guidelines, enabling definitive classification of the variants as pathogenic or likely pathogenic. This case expands the phenotypic spectrum of FAM149B1-related disorders to include isolated urinary tract malformations in the prenatal period, where neurological manifestations may be absent or subtle. Our findings highlight the utility of prenatal exome sequencing in atypical cases and contribute to the understanding of the expanding genetic and phenotypic landscape of ciliopathies.
BACKGROUND
Nonimmune factors are the most common cause of fetal hydrops, which are characterized by the accumulation of pathological fluid due to various causes. The etiology of this disease is complex, with a relatively high mortality rate, and the prognosis largely depends on the underlying cause. Notably, fetal hydrops attributable to genetic causes, such as chromosomal abnormalities or gene mutations, are typically associated with a poor prognosis.
CASE PRESENTATION
A fetus diagnosed with severe nonimmune fetal hydrops at 27 weeks of gestation presented with multiple abnormalities on prenatal ultrasound, including progressively thickened nuchal translucency (NT) and nuchal fold (NF), cystic hygroma, pleural effusion, and renal pelvis duplication. Amniotic fluid cytogenetic analysis revealed a normal karyotype. Integrated chromosomal microarray analysis (CMA) and trio-based whole-exome sequencing (Trio-WES) revealed a pathogenic 2.82 Mb duplication at chromosome 22q11.21, designated as arr[GRCh37] 22q11.21(18984188-21804597)x3, associated with 22q11.2 duplication syndrome, which was inherited from the father. Additionally, a heterozygous missense variant in the LZTR1 gene NM_006767.3: c.848G > A (p.Arg283Gln) was detected and classified as pathogenic, associated with Noonan syndrome type 10, maternally inherited. After comprehensive counseling and careful consideration, the parents elected to terminate the pregnancy.
CONCLUSION
This study revealed that fetuses carrying both a pathogenic copy number variant of duplication in the 22q11.2 region and a heterozygous pathogenic missense variant of the LZTR1 gene (c.848G > A) simultaneously constitute the main genetic basis for its multisystem abnormalities and severe hydrops. This study highlights the role of multiple genetic superimposition effects in the formation of complex fetal phenotypes and emphasizes that in genetic counseling and prenatal diagnosis, a combined strategy of CMA and Trio-WES should be adopted to improve the detection rate of complex genetic diseases and the accuracy of recurrence risk assessment.
Zhangxiang Zou, Zhechao Zhang, Yanchou Ye et al.· BMC Pregnancy and Childbirth· 0 citations
Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities.
We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the
POR
gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in
cis
, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)–binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)–binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS).
This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.
Wen-Ting Zhang, Jun-Feng Zeng, Yan-Jing Li et al.· Frontiers in Endocrinology· 0 citations
Background Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by pathogenic variants in PKD1. Here, we reported the functional characterization of an intronic PKD1 variant identified in an ADPKD-affected family and its subsequent application in preimplantation genetic testing for monogenic disorders (PGT-M). Case presentation A three-generation ADPKD family was enrolled. Whole-exome sequencing revealed a heterozygous PKD1 c.7489 + 5G>A variant, which co-segregated with the disease and was initially classified as a variant of uncertain significance. A minigene assay demonstrated that the variant induced skipping of exon 18, leading to a frameshift (p.Arg2404Valfs*123), supporting its reclassification as pathogenic. The couple underwent PGT-M using trophectoderm biopsy, haplotype linkage analysis, and direct mutation detection. An unaffected pregnancy was achieved, and subsequent prenatal diagnosis confirmed the absence of the variant and a normal chromosomal karyotype. Conclusion We validated a pathogenic splicing variant in PKD1 and successfully applied PGT-M to prevent disease transmission, resulting in an unaffected pregnancy.
Qiong Pan, Yuefang Liu, Xueping Sun et al.· Frontiers in Genetics· 0 citations
This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
Introduction Renal coloboma syndrome (RCS) is an autosomal dominant disorder caused by pathogenic variants in the PAX2 gene, primarily affecting renal and optic nerve development. However, the presentation of RCS is highly heterogeneous, ranging from mild renal anomalies to severe multi‐organ involvement. This phenotypic variability often poses significant challenges for accurate clinical diagnosis. Case Presentation In this study, a novel heterozygous PAX2 missense mutation (NM_000278.5: c.404 T > G, p.Ile135Ser) was identified via whole‐exome sequencing (WES) in a 31‐year‐old pregnant woman and her fetus. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this mutation is classified as likely pathogenic. The phenotypic divergence observed between the mother and neonate underscores the syndrome′s variable penetrance. While the mother exhibited relatively mild renal and optic nerve anomalies, the neonate presented with severe multi‐organ involvement, including renal structural defects, hearing impairment, and extensive pulmonary, cardiac, and cerebral lesions, culminating in fatal intracranial hemorrhage and multi‐organ failure at 2 months of age. Discussion The present case identified a previously unreported pathogenic variant in the PAX2 gene, thereby expanding the mutational spectrum of PAX2‐related RCS. It also further underscores the phenotypic heterogeneity of this disorder, even among members of the same family. Additionally, the genotype–phenotype spectrum of PAX2‐related cases was also reviewed to facilitate early diagnosis, management, and genetic counseling for RCS.
G. Wang, Jie Wang, Lichun Zhang et al.· Case Reports in Obstetrics a...· 0 citations
