Sex‐limited penetrance of lymphedema to females with <i>CELSR1</i> haploinsufficiency: A second family

Erickson, Robert P.; Lai, Li‐Wen; Mustacich, Debbie J.; Bernas, Michael; Kuo, Phillip H.; Witte, Marlys H.

doi:10.1111/cge.13622

Cited by 25 publications

(30 citation statements)

References 7 publications

(16 reference statements)

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“…Inclusion of additional adolescents and adults may help clarify this finding. Heterozygous loss-of-function variants in CELSR1 have been reported in individuals with hereditary lymphedema ( 42 , 43 ). CELSR1 is located at 22q13.31 and is included in 22q13 terminal deletions larger than 4.3 Mb.…”

Section: Discussionmentioning

confidence: 99%

Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Levy

Foss‐Feig

Betancur

et al. 2021

Human Molecular Genetics

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Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive, and behavioral abnormalities. Previous literature has begun to elucidate genotype–phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype–phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (include SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions), or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype–phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories, and comorbidities as a function of specific genetic alteration.

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Section: Discussionmentioning

confidence: 99%

Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Levy

Foss‐Feig

Betancur

et al. 2021

Human Molecular Genetics

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“…While the distichiasis can be evident from birth, the lymphedema of the lower limbs usually develops late in childhood or later in life and sometimes not until the 5th decade, although (very rarely) congenital onset cases have been reported (115). Nonimmune fetal hydrops has also been observed (100,105,131). The lymphedema of the lower limbs is most commonly bilateral.…”

Section: Human Phenotypementioning

confidence: 99%

Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema

Martin-Almedina

Mortimer

Østergaard

2021

Physiological Reviews

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Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focusses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic gene dysfunction can affect immune function so leading to infection; it can influence cancer development and spread; and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological function of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

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“…In 2016, Gonzalez-Galay et al [22] reported a family with symptomatic hereditary lymphedema across three generations based on a proband with a mutation in CELSR1. In 2019, Erickson et al [23] reported a family with CELSR1 haploinsu ciency in which lymphedema affected only the female members, and the patients presented with lymphangiectasia, valve dysfunction, and thoracic duct re ux. In 2021, Xia et al [24] reported that a CELSR1 deletion could be associated with lymphatic dysplasia in a lymphedema patient with 22q13.3 deletion syndrome.…”

Section: Discussionmentioning

confidence: 99%

Clinical Staging and Genetic Profiling of Korean Patients with Primary Lymphedema Using Whole-Exome Sequencing: Preliminary Results

Seo

Lee

Park

et al. 2022

Preprint

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Lymphedema is a progressive disease caused by lymphatic flow blockage in the lymphatic pathway. Primary (hereditary) lymphedema is caused by genetic mutations without secondary causes. However, the underlying cause of primary lymphedema remains obscure, and gene sequencing studies on a sizable patient cohort are lacking. We performed clinical profiling on Korean primary lymphedema patients based on their phenotypes and using lymphoscintigraphy and made genetic diagnoses using a next-generation sequencing panel consisting of 60 lymphedema-related genes. Of 27 patients, 21% had lymphedema of the upper extremities, 81% had lymphedema of the lower extremities, and two patients had lymphedema in both. Based on International Society of Lymphology staging, 14, 10, and 3 patients had stage 3, 2, and 1 lymphedema, respectively. Genetic abnormalities were identified in six patients: a pathogenic variant of CELSR1 in two patients, variants of uncertain significance (VUSs) of CELSR1 in two patients, a VUS of SOS1 in one patient, and a pathogenic variant of MPI and VUSs of TIE1, FLT4, and PIEZO1 in one patient. The clinical and genetic profile of hereditary lymphedema reported here is the first such data series reported in South Korea. Our study highlights the need for genetic screening in primary lymphedema diagnosis.

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Sex‐limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family

Cited by 25 publications

References 7 publications

Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema

Clinical Staging and Genetic Profiling of Korean Patients with Primary Lymphedema Using Whole-Exome Sequencing: Preliminary Results

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