American Journal of Medical Genetics Part A最新文献

{"title":"Monochorionic, Dizygotic, Sex Discordant Twins With Twin Anemia Polycythemia Sequence.","authors":"Julie T Alan, Lauren N Meiss, Jena L Miller, Michelle Kush, Angie C Jelin, Ahmet A Baschat, Mara Rosner","doi":"10.1002/ajmg.a.64278","DOIUrl":"https://doi.org/10.1002/ajmg.a.64278","url":null,"abstract":"<p><p>Monochorionic twins are typically monozygotic with identical fetal sex. We present a monochorionic, diamniotic twin pair of a triplet gestation with discordant fetal sex also affected with twin anemia polycythemia sequence (TAPS). The pregnancy was conceived with ovulation induction, and the initial ultrasound at 8 weeks revealed a dichorionic triamniotic triplet gestation. Discordant sex between the monochorionic pair was noted on ultrasound at 20 weeks, with Fetus 1 appearing phenotypically female and Fetus 2 appearing phenotypically male. At 26 weeks, the middle cerebral artery peak systolic velocity discordance between the monochorionic pair met criteria for stage II TAPS, a condition produced by unequal sharing of red blood cells across small diameter vascular anastomoses on the monochorionic placenta. Subsequent fetal blood sampling demonstrated hemoglobin of 8.2 g/dL of the donor twin, Fetus 2, and intrauterine transfusion was performed. Rapid progression to stage III TAPS was noted at 29 weeks, and delivery was recommended. The triplets were delivered via uncomplicated primary cesarean delivery. Triplet 1 had female genitalia at birth and Triplet 2 had male genitalia. Placental histology demonstrated a dichorionic, triamniotic placenta confirming monochorionicity for Fetus 1 and 2. Fluorescence in situ hybridization of the nucleated peripheral blood cells for Triplet 1 demonstrated 61% XX and 39% XY. In Triplet 2, FISH demonstrated 56% XX and 44% XY. Chromosomal microarray analysis conducted from buccal swabs collected 6 days after birth revealed that the sex chromosome complement for triplet 1 matched the female appearing genitalia {XX [arr(X,1-22)x2]} and for triplet 2 matched the male genitalia {XY [arr(X,Y)x1, (1-22)x2]}, with no mosaicism. Results confirm a trizygotic triplet pregnancy with a functionally monochorionic placenta for the twin pair presenting with TAPS, with direct evidence of shared blood across in utero anastomosis on the placenta. This rarely reported phenomenon may be secondary to close implantation or fusion of distinct embryos with the development of vascular anastomoses.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64278"},"PeriodicalIF":1.7,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo Heterozygous ZFX Frameshift Variant in a Female With an X-Linked Neurodevelopmental Disorder.","authors":"Iftekhar A Showpnil, Allison Daley, Emily R Sites, Shayne M Plourde, Jesse M Hunter, Dennis W Bartholomew, April N Lehman, Daniel C Koboldt, Rolf W Stottmann","doi":"10.1002/ajmg.a.64280","DOIUrl":"https://doi.org/10.1002/ajmg.a.64280","url":null,"abstract":"<p><p>Germline ZFX variants are associated with an X-linked neurodevelopmental disorder, with 14 males and 16 females reported to date. We describe a 20-year-old female with a heterozygous ZFX frameshift variant, p.(Met666Valfs*2), identified by genome sequencing, previously reported in an affected male. She exhibited motor and speech delays with hypotonia in early childhood, and was later diagnosed with congenital heart defects, autism spectrum disorder, mild intellectual disability, and absence seizures. She further developed sensorineural hearing loss, skin hyperpigmentation, and ophthalmoplegia. Novel phenotypic features included inferior cerebellar vermian hypoplasia, hypoplastic right vertebral artery, aberrant subclavian artery, long palpebral fissures, ophthalmoplegia, skin hyperpigmentation, and a short uvula, expanding the known clinical spectrum. Female carriers of pathogenic ZFX variants demonstrate highly variable expressivity, ranging from apparently unaffected individuals to syndromic presentations. Individuals with heterozygous missense variants often exhibit hyperparathyroidism, suggesting a genotype-phenotype correlation. Reanalysis of published RNA-sequencing data identified 15 ZFX target genes involved in neurodevelopment, suggesting a role for these genes in disease pathogenesis. These findings confirm the pathogenicity of the p.(Met666Valfs*2) variant in the proband and highlight the phenotypic heterogeneity of the disorder in females. Clinical care should include cardiac and endocrine monitoring, with endocrine testing offered to unaffected females carrying missense variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64280"},"PeriodicalIF":1.7,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The HRAS Variant c.175G>A (p.Ala59Thr) Causes a Predominantly Ectodermal Phenotype Lacking Classic Costello Syndrome Features.","authors":"Nikole Rautiainen, Eveliina Brandt, Kaisa Kettunen, Outi Elomaa, Sirpa Kivirikko, Leila Jeskanen, Katriina Lappalainen, Nelli Sjöblom, Juha Kere, Katariina Hannula-Jouppi, Liisa Harjama","doi":"10.1002/ajmg.a.64277","DOIUrl":"https://doi.org/10.1002/ajmg.a.64277","url":null,"abstract":"<p><p>Costello syndrome (CS) is a rare dominant HRAS RASopathy characterized by curly hair, cardiac abnormalities, craniofacial anomalies, and developmental delay. HRAS codon 58, 59, and 60 variants are associated with milder phenotypes. We describe a three-generation family with a previously unreported heterozygous HRAS variant c.175G>A (p.Ala59Thr) causing a predominantly ectodermal phenotype. Exome and Sanger sequencing were used for genetic analysis. Dermatological and cardiac evaluations were performed, including skin biopsy and hair sample microscopy. A 14-year-old proband, her twin sister, mother, mother's father, and mother's paternal half-brother all shared a phenotype of woolly and sparse hair, curly eyelashes, sparse eyebrows, ulerythema ophryogenes, keratosis pilaris, palmoplantar keratoderma, and low-set posteriorly rotated ears. One patient required a gastrostomy after birth but otherwise classic CS features, including craniofacial anomalies, hypertrophic cardiomyopathy, and intellectual disability, were absent. We conducted a comparison supporting the attenuated CS phenotype associated with HRAS codon 58-60 variants. In conclusion, HRAS c.175G>A (p.Ala59Thr) causes predominantly an ectodermal phenotype, consistent with milder HRAS-related RASopathies involving codons 58-60 distinguishable from classic CS. HRAS variants should be considered in patients with ectodermal and CS-like features for accurate genetic diagnosis and targeted management.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64277"},"PeriodicalIF":1.7,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caregiver Perceived Barriers to Diagnosis and Care in Down Syndrome Regression Disorder.","authors":"Anya Alag, Nicole A Nishimori, Lilia Kazerooni, Maeve C Lucas, David J Huh, Mariam M Yousuf, Saba Jafarpour, Cathy Franklin, Eileen A Quinn, Jonathan D Santoro","doi":"10.1002/ajmg.a.64274","DOIUrl":"https://doi.org/10.1002/ajmg.a.64274","url":null,"abstract":"<p><p>Down Syndrome Regression Disorder (DSRD) is a rare neuropsychiatric condition affecting individuals with Trisomy 21. Barriers to care for DSRD patients have not been studied. This research aimed to explore how demographic, socioeconomic, and geographic factors influence access to diagnosis, testing, and treatment for individuals with DSRD. A cross-sectional, online, REDCap survey was utilized to query caregivers of individuals with DSRD. Eligible caregivers answered questions regarding demographics, clinical features, and barriers to diagnosis and treatment. Statistical analysis was performed using R software, employing χ², Mann-Whitney U, and Kruskal-Wallis H tests. A total of 397 participants were enrolled, most from the US (74%). Barriers to diagnosis (58.1%), treatment (52.6%), referral (52.0%), and testing (39.4%) were prevalent. Key barriers included physician unfamiliarity with DSRD and a lack of local specialists. Travel distances for diagnosis, testing, and treatment were significant, with 14.7% traveling over 500 miles for diagnosis and some requiring international travel. Factors influencing delays in diagnosis and treatment included household income, region, and demographic variables. Higher income was associated with shorter time to diagnosis (p = 0.004) and treatment (p < 0.001). Race, income, maternal education, and setting influenced delays in diagnosis. Delays in treatment were influenced by ethnicity, income, and location. This large international survey of caregivers of individuals with DSRD elucidates perceived barriers to accessing diagnosis, testing, and treatment, with demographic factors such as socioeconomic status and geography influencing these challenges. The directionality of these effects and their impact on clinical care and outcomes will be a logical basis for additional studies. Further studies are needed to explore these barriers in greater depth and assess their impact on healthcare outcomes.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64274"},"PeriodicalIF":1.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Table of Contents, Volume 197A, Number 11, November 2025","authors":"","doi":"10.1002/ajmg.a.63771","DOIUrl":"https://doi.org/10.1002/ajmg.a.63771","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 11","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.63771","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Head Circumference Height Index (HCH-I) to Quantify Relative Macrocephaly and Aid Identification of Hypochondroplasia in Children.","authors":"Moira S Cheung, Ruggero Lanzafame, Karen J Low, Tim J Cole","doi":"10.1002/ajmg.a.64266","DOIUrl":"https://doi.org/10.1002/ajmg.a.64266","url":null,"abstract":"<p><p>Hypochondroplasia (HCH) is a rare skeletal dysplasia caused by pathogenic variants in the FGFR3 gene. We hypothesized that the relative disproportion between head circumference and height in HCH might be diagnostically informative and generated a simple index of head-stature disproportion to help pediatricians diagnose HCH. The Head Circumference Height Index (HCH-I), based on formal statistical principles, is defined as height Z-score - 1/2 head circumference Z-score, with the Z-scores based here on the UK90 growth reference. An HCH-I below the cut-off of -2 indicates substantial head-height disproportion. We validated the index by comparing children diagnosed with HCH (n = 364), using data from the recent European HCH growth charts, to children from the Cambridge Infant Growth Study (CIGS) (n = 4620). The mean (SD) HCH-I was -3.0 (1.2) in the HCH cohort, compared to -0.2 (0.9) in the CIGS cohort. An HCH-I below -2 correctly identified 78% of children with HCH, while only 2.4% of CIGS children fell below the cut-off. An HCH-I below -2 identifies children with head-height disproportion who may have HCH or another genetic disorder. The index is deliberately simple to calculate and should prove useful in clinical practice.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64266"},"PeriodicalIF":1.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Collaborative Approach to Pediatric Genetic Evaluation in the Era of Genomic Medicine.","authors":"Sarah Jurgensmeyer Langas, Allison Goetsch Weisman, Valerie Allegretti, Katherine Kim, Roxanne Birriel, Carlos E Prada","doi":"10.1002/ajmg.a.64276","DOIUrl":"https://doi.org/10.1002/ajmg.a.64276","url":null,"abstract":"<p><p>To address the increased demand for genetic services and shortage of medical geneticists (MG), a collaborative pilot program was developed with a two-part approach to care: (1) Initial genetic counselor (GC) appointment with exome sequencing (ES) and (2) follow-up MG evaluation. Nonemergent genetics referrals were reviewed by a GC for eligibility and approved by a MG. The GC appointment included comprehensive medical intake, family history, and ES consent. The GC disclosed ES results, and patients were scheduled for MG evaluation. Forty-five patients were evaluated, with 42 completing ES (93.3%). The program reduced wait time for nonemergent genetics evaluation (12-21 months to 1-5 months) and decreased the no-show rate (9.3%-4.8%). Most patients spoke English (82.2%) and had public insurance (55.6%). ES identified diagnostic likely pathogenic or pathogenic variants in 28.6% (12/42) of patients and clinically suspicious variants of uncertain significance in 19.0% (8/42). There were changes in medical management for 42.9% (18/42) of patients. No patients declined scheduling into this clinic, and limited survey responses indicated family satisfaction. This pilot was effective in decreasing wait times, was well received by families, and expanded genetics access for a single-center pediatric institution with sufficient GC staffing.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64276"},"PeriodicalIF":1.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo Variants in PPFIA2 in Individuals With Neurodevelopmental Disorders.","authors":"Theresa Brunet, Michael Zech, Ulrich A Schatz, Miriam Adamovičová, Matias Wagner, Elisabeth Graf, Riccardo Berutti, Heike Weigand, Robert Jech, Thomas Meitinger, Juliane Winkelmann, Melanie Brugger","doi":"10.1002/ajmg.a.64255","DOIUrl":"https://doi.org/10.1002/ajmg.a.64255","url":null,"abstract":"<p><p>Liprin-α2, encoded by PPFIA2, belongs to the family of Liprin-α proteins which constitute major synaptic scaffolds participating in the assembly and maturation of synapses. Heterozygous de novo variants in PPFIA2 were identified by exome or genome sequencing in two unrelated individuals with a neurodevelopmental disorder. The hypothesis of PPFIA2 as a novel candidate gene for a neurodevelopmental disorder is supported by the gnomAD gene constraint metrics and further strengthened by our identification of seven additional individuals in large cohort studies carrying rare de novo variants and presenting with overlapping phenotype. In summary, we provide evidence for the second gene-disease association of a Liprin-α protein beyond PPFIA3.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64255"},"PeriodicalIF":1.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel and Rare Gene Variants in Cleft Lip/Palate Patients From Kuwaiti Consanguineous Families by Exome Sequencing.","authors":"Lateefa Alkharafi, Suzanne Al-Bustan, Sumaya Alkanderi, Reem M Elshafie, Heba Dannoun, Hadil Alrohaif, Alaa-Eldin Elshafey, Amal Alwadani, Saud Alhasawi, Nour Aljeraiwi, Khaled Alotaibi, Hala Hamdan, Dedeepya Vaka, Ugur Hodoglugil, Dario Boffelli, Kimberly K Diaz Perez, Elizabeth J Leslie-Clarkson, Ophir D Klein","doi":"10.1002/ajmg.a.64268","DOIUrl":"https://doi.org/10.1002/ajmg.a.64268","url":null,"abstract":"<p><p>The prevalence of Cleft Lip with or without Cleft Palate (CLP) varies by geography and ethnicity, particularly in consanguineous populations. This study aimed to identify gene variants contributing to the development of both syndromic (SCLP) and non-syndromic (NSCLP) forms of the condition in 20 consanguineous Kuwaiti families. We used exome sequencing and assessed the variants' predicted functional roles. Seven rare gene variants were identified across all cases, including one novel variant (LRRC32) in a syndromic case and three variants (SH3PXD2A, DUOX1, MSX2) in non-syndromic cases. These genes are predicted to be involved in cellular metabolism, differentiation, signaling, and regulatory mechanisms. Four genes (SH3PXD2A, DUOX1, MSX2, and ACACB) identified in the non-syndromic cases were found to have a significant association with co-expression of the transcription factor TP63. These findings provide a foundation for further investigation into the functional roles of these novel variants in the development of NSCLP, particularly DUOX1, which has not been previously reported in CLP.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64268"},"PeriodicalIF":1.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZMIZ1-Associated Neurodevelopmental Disorder in a 52-Year-Old Woman.","authors":"Sila Rogan, Anthony Gador, Evelyn Carroll, Jan M Friedman","doi":"10.1002/ajmg.a.64243","DOIUrl":"https://doi.org/10.1002/ajmg.a.64243","url":null,"abstract":"<p><p>Variants in ZMIZ1 can cause a syndromic neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies. Here we report a woman with a de novo ZMIZ1 c.899C>T (p.Thr300Met) variant, low average IQ, high myopia, craniofacial dysmorphisms, genitourinary anomalies, cardiac defects, lower limb deformities, and chronic pain. She died unexpectedly at 52 years of age. Additional findings seen on autopsy included cerebral cortical neuronal heterotopias. Our report illustrates that individuals with ZMIZ1-associated neurodevelopmental disorder can lead long, active, and fulfilling lives.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64243"},"PeriodicalIF":1.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}