Genetically isolated populations that arise due to recent bottleneck events have reduced genetic variation reflecting the common set of founders. Increased genetic relatedness among members of isolated populations puts them at increased risk for some recessive disorders that are rare in outbred populations. To assess the burden on reproductive health, we compared frequencies of adverse reproductive outcomes between Amish couples who were both heterozygous carriers of a highly penetrant pathogenic or likely pathogenic variant and noncarrier couples from the same Amish community. In addition, we evaluated whether overall genetic relatedness of parents was associated with reproductive outcomes. Of the 1824 couples included in our study, 11.1% were at risk of producing a child with an autosomal recessive disorder. Carrier couples reported a lower number of miscarriages compared to noncarrier couples (p = 0.02), although the number of stillbirths (p = 0.3), live births (p = 0.9), and number of pregnancies (p = 0.9) did not differ significantly between groups. In contrast, higher overall relatedness between spouses was positively correlated with number of live births (p < 0.0001), pregnancies (p < 0.0001), and stillbirths (p = 0.03), although not with the number of miscarriages (p = 0.4). These results highlight a complex association between relatedness of parents and reproductive health outcomes in this community.
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Topic
- Cardiac System
- Clinical Case Report
- Diagnostic Development
- Disease Discovery
- Endocrine System
- Endophenotype
- Genomic Testing
- Hearing
- Hepatic System
- Immune System
- Laboratory
- Metabolic
- Mitochondrial
- Natural History
- Neurologic System
- Ocular System
- Opinion
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- Population Genetics
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- Year
Published Papers
The primary goal of our research will always be to find effective and affordable treatments for patients. One of the central focus areas of our mission is sharing our methods and discoveries with the broader scientific community.
In the over 35 years since the Clinic's founding, our staff have published more than 130 peer-reviewed research papers, fueled by close collaboration between our clinical and laboratory teams and effective relationships with academic, scientific, and clinical partners.
Authors: Katie B Williams, Michael Horst, Millie Young, Christine Pascua, Erik G Puffenberger, Karlla W Brigatti, Claudia Gonzaga-Jauregui, Alan R Shuldiner, Samuel Gidding, Kevin A Strauss, Devyani Chowdhury
Familial hypercholesterolemia (FH) due to a founder variant in Apolipoprotein B (ApoBR3500Q) is reported in 12% of the Pennsylvania Amish community. By studying a cohort of ApoBR3500Q heterozygotes and homozygotes, we aimed to characterize the biochemical and cardiac imaging features in children and young adults with a common genetic background and similar lifestyle.
Authors: Sem J Aronson, Norman Junge, Mediha Trabelsi, Wided Kelmemi, Aurelie Hubert, Karlla W Brigatti, Michael D Fox, Robert J de Knegt, Johanna C Escher, Virginia M Ginocchio, Raffaele Iorio, Yan Zhu, Figen Ozcay, Fakher Rahim, Mortada H F El-Shabrawi, Eyal Shteyer, Angelo Di Giorgio, Lorenzo D'Antiga, Federico Mingozzi, Nicola Brunetti-Pierri, Kevin A Strauss, Philippe Labrune, Ridha Mrad, Ulrich Baumann, Piter J Bosma, CureCN Consortium
Authors: Philip H Iffland, Mariah E Everett, Katherine M Cobb-Pitstick, Lauren E Bowser, Allan E Barnes, Janice K Babus, Andrea J Romanowski, Marianna Baybis, Soad Elziny, Erik G Puffenberger, Claudia Gonzaga-Jauregui, Alexandros Poulopoulos, Vincent J Carson, Peter B Crino
Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mechanistic target of rapamycin (mTOR) pathway, are associated with epilepsy and malformations of cortical development.
Authors: Vincent J Carson, Millie Young, Karlla W Brigatti, Donna L Robinson, Robert M Reed, Jihee Sohn, Marco Petrillo, Wildon Farwell, Freeman Miller, Kevin A Strauss
Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease.
Authors: Cole J. Ferguson, Olivia Urso, Tatyana Bodrug, Brandon M. Gassaway, Edmond R. Watson, Jesuraj R. Prabu, Pablo Lara-Gonzalez, Raquel C. Martinez-Chacin, Dennis Y. Wu, Karlla W. Brigatti, Erik G. Puffenberger, Cora M. Taylor, Barbara Haas-Givler, Robert N. Jinks, Kevin A. Strauss, Arshad Desai, Harrison W. Gabel, Steven P. Gygi, Brenda A. Schulman, Nicholas G. Brown, Azad Bonni
Authors: Sarah A F Henkel, Claudia M Salgado, Miguel Reyes-Mugica, Kyle A Soltys, Kevin Strauss, George V Mazariegos, Robert H Squires, Patrick J McKiernan, Xingyu Zhang, James E Squires
Background: Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts.
Methods: We assessed 7 PFIC1 patients post-LT at the Children’s Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test.
Results: Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis.
Conclusion: We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.
Authors: Erik G. Puffenberger
Founder populations have long contributed to our knowledge of rare disease genes and phenotypes. From the pioneering work of Dr. Victor McKusick to today, research in these groups has shed light on rare recessive phenotypes, expanded the clinical spectrum of disease, and facilitated disease gene identification. Current clinical and research studies in these special groups augment the wealth of knowledge already gained, provide new insights into emerging problems such as variant interpretation and reduced penetrance, and contribute to the development of novel therapies for rare genetic diseases. Clinical developments over the past 30 years have altered the fundamental relationship with the Lancaster Plain communities: research has become more collaborative, and the knowledge imparted by these studies is now being harnessed to provide cutting-edge translational medicine to the very community of vulnerable individuals who need it most.
Support our mission of providing compassionate, affordable, and efficient care to families facing rare genetic disorders!
Our clinic serves as a trusted medical practice for children and adults facing rare genetic disorders. Our dedicated team works every day to prevent and treat genetic illnesses. Our facility is in the heart of the Amish and Mennonite communities in Lancaster County. Inside is filled with cutting-edge gene sequencing tools that allow us to deliver highly personalized care—a precise treatment option for the right patient at the right time.