Kenny–Caffey syndrome type 2

Yerawar, Chaitanya; Kabde, Aditi; Deokar, Prerana

doi:10.1093/qjmed/hcaa175

Cited by 12 publications

(8 citation statements)

References 4 publications

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“…revealed in the present study has been previously reported in 14 cases worldwide (Abraham et al, 2017;Grosse et al, 2017;Guo et al, 2014;Isojima et al, 2014;Nikkel et al, 2014;Unger et al, 2013;Wang et al, 2019;Yerawar, Kabde, & Deokar, 2020).…”

Section: Discussionsupporting

confidence: 83%

“…The variable ID phenotype in KCS1 and SSS has been reported worldwide (Albaramki et al, 2012; Diaz et al, 1999; Haider et al, 2014; Kelly, 2000; Sanjad et al, 1991). The heterozygous de novo c.1706G>A (p.Arg569His) variant in FAM111A revealed in the present study has been previously reported in 14 cases worldwide (Abraham et al, 2017; Grosse et al, 2017; Guo et al, 2014; Isojima et al, 2014; Nikkel et al, 2014; Unger et al, 2013; Wang et al, 2019; Yerawar, Kabde, & Deokar, 2020). None of these patients were described with microcephaly and/or ID, and most were independent studies, with no familial relationship between the patients, except a report on a mother and daughter by Nikkel et al (2014).…”

Section: Discussionsupporting

confidence: 76%

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Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

Cavole

Perrone

Soares

et al. 2020

American J of Med Genetics Pt A

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Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 76%

Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

Cavole

Perrone

Soares

et al. 2020

American J of Med Genetics Pt A

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“…Diagnosis of skeletal dysplasias is challenging, especially prenatally, due to limitations of prenatal imaging, variable expressivity, and significant clinical overlap (Best et al, 2018). The expanding genetic testing, including WES, has aided in identifying molecular causes of skeletal dysplaisas including identifying mutations in the FAM111A gene as the molecular cause of KCS2 and OCS (Abraham et al, 2017; Isojima et al, 2014; Nikkel et al, 2014; Turner et al, 2020; Unger et al, 2013; Yerawar et al, 2020). However, due to the rarity of the condition, the mutational spectrum of FAM111A ‐related syndromes remains narrow.…”

Section: Discussionmentioning

confidence: 99%

“…While in silico prediction models predicted tolerated effect on protein function, the R569H mutation is also predicted to be tolerated by various prediction models (Isojima et al, 2014; Yerawar et al, 2020). This difference may be due to mutations having a gain of function mechanism of pathogenesis, which may be more difficult to predict by in silico modeling.…”

Section: Discussionmentioning

confidence: 99%

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull

Müller

Steffensen

Krstić

et al. 2021

American J of Med Genetics Pt A

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Kenny‐Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A‐related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A‐related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

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“…Mutations in the FAM111A gene were found to be the primary cause of Kenny-Caffey Syndrome type 2 (KCS2) and the more severe disorder Gracile Bone Dysplasia (GCLEB), also known as osteocraniostenosis ( Figure 1A ) ( Kenny and Linarelli, 1966 ; Caffey, 1967 ; Unger et al, 2013 ; Guo et al, 2014 ; Isojima et al, 2014 ; Nikkel et al, 2014 ; Kim et al, 2015 ; Abraham et al, 2017 ; Wang et al, 2019 ; Cavole et al, 2020 ; Deconte et al, 2020 ; Pemberton et al, 2020 ; Turner et al, 2020 ; Cheng et al, 2021 ; Eren et al, 2021 ; Lang et al, 2021 ; Muller et al, 2021 ; Yerawar et al, 2021 ; Rosato et al, 2022 ). In both diseases, patients present with stenosis and thickening of long bones, hypoparathyroidism, hypocalcemia, and short stature.…”

Section: Fam111a Mutations In Genetic Diseasesmentioning

confidence: 99%

Functions and evolution of FAM111 serine proteases

Welter

Machida

2022

Front. Mol. Biosci.

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Proteolysis plays fundamental and regulatory roles in diverse cellular processes. The serine protease FAM111A (FAM111 trypsin-like peptidase A) emerged recently as a protease involved in two seemingly distinct processes: DNA replication and antiviral defense. FAM111A localizes to nascent DNA and plays a role at the DNA replication fork. At the fork, FAM111A is hypothesized to promote DNA replication at DNA-protein crosslinks (DPCs) and protein obstacles. On the other hand, FAM111A has also been identified as a host restriction factor for mutants of SV40 and orthopoxviruses. FAM111A also has a paralog, FAM111B, a serine protease with unknown cellular functions. Furthermore, heterozygous missense mutations in FAM111A and FAM111B cause distinct genetic disorders. In this review, we discuss possible models that could explain how FAM111A can function as a protease in both DNA replication and antiviral defense. We also review the consequences of FAM111A and FAM111B mutations and explore possible mechanisms underlying the diseases. Additionally, we propose a possible explanation for what drove the evolution of FAM111 proteins and discuss why some species have two FAM111 proteases. Altogether, studies of FAM111 proteases in DNA repair, antiviral defense, and genetic diseases will help us elucidate their functions and the regulatory mechanisms.

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Kenny–Caffey syndrome type 2

Cited by 12 publications

References 4 publications

Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull

Functions and evolution of FAM111 serine proteases

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