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

Müller, Réka; Steffensen, Thora S.; Krstić, Nevena; Cain, Mary Ashley

doi:10.1002/ajmg.a.62182

Cited by 9 publications

(8 citation statements)

References 24 publications

(42 reference statements)

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“…Most variants are clustered together near the protein C-terminus, and a definite genotype-phenotype correlation, explaining the different severity of OCS and KCS, has not been established yet. [33], Ser541Tyr/Pro were reported in [5,32], respectively, Tyr562Ser was reported in [21], while all other variants were observed at the Laboratory of Genetics at CHUV ( [7] and this report). The domain in orange has homology to trypsin-like peptidases, including an untested catalytic triad purportedly composed of Ser541/His385/Asp439 (red bars).…”

Section: Discussionmentioning

confidence: 50%

“… Scheme of the FAM111A protein and known pathogenic variants associated with either osteocraniostenosis (OCS, top ) or Kenny-Caffey syndrome (KCS, bottom ). Cys485Phe was reported in [ 33 ], Ser541Tyr/Pro were reported in [ 5 , 32 ], respectively, Tyr562Ser was reported in [ 21 ], while all other variants were observed at the Laboratory of Genetics at CHUV ([ 7 ] and this report). The domain in orange has homology to trypsin-like peptidases, including an untested catalytic triad purportedly composed of Ser541/His385/Asp439 (red bars).…”

Section: Figurementioning

confidence: 86%

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Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

Rosato

Unger²,

Campos‐Xavier³

et al. 2022

Genes

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Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny‐Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

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Section: Discussionmentioning

confidence: 50%

Section: Figurementioning

confidence: 86%

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

Rosato

Unger²,

Campos‐Xavier³

et al. 2022

Genes

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“…The search keywords included "Kenny−Caffey syndrome type 2" or "FAM111A". The available data on clinical evaluations and genetic findings were extracted and summarized (Table 1) (10,11,16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Section: Literature Reviewmentioning

confidence: 99%

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Ohmachi

Urai²,

Bando³

et al. 2023

Front. Endocrinol.

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Kenny–Caffey syndrome type 2 (KCS2) is an extremely rare skeletal disorder involving hypoparathyroidism and short stature. It has an autosomal dominant pattern of inheritance and is caused by variants in the FAM111 trypsin-like peptidase A (FAM111A) gene. This disease is often difficult to diagnose due to a wide range of more common diseases manifesting hypoparathyroidism and short stature. Herein, we present the case of a 56-year-old female patient with idiopathic hypoparathyroidism and a short stature. The patient was treated for these conditions during childhood. Upon re-evaluating the etiology of KCS2, we suspected that the patient had the disorder because of clinical manifestations, such as cortical thickening and medullary stenosis of the bones, and lack of intellectual abnormalities. Genetic testing identified a heterozygous missense variant in the FAM111A gene (p.R569H). Interestingly, the patient also had bilateral sensorineural hearing loss and vestibular dysfunction, which have been rarely described in previous reports of pediatric cases. In KCS2, inner ear dysfunction due to Eustachian tube dysfunction may progress in middle age or later. However, this disease is now being reported in younger patients. Nevertheless, our case may be instructive of how such cases emerge chronically after middle age. Herein, we also provide a literature review of KCS2.

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

Cited by 9 publications

References 24 publications

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Functions and evolution of FAM111 serine proteases

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