Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants

被引:11
作者
Leonardi, Emanuela [1 ,2 ,3 ]
Aspromonte, Maria Cristina [1 ,2 ,3 ]
Drongitis, Denise [4 ]
Bettella, Elisa [1 ,2 ]
Verrillo, Lucia [4 ]
Polli, Roberta [1 ,2 ]
McEntagart, Meriel [5 ]
Licchetta, Laura [6 ]
Dilena, Robertino [7 ]
D'Arrigo, Stefano [8 ]
Ciaccio, Claudia [8 ]
Esposito, Silvia [8 ]
Leuzzi, Vincenzo [9 ]
Torella, Annalaura [10 ,11 ]
Baldo, Demetrio [12 ]
Lonardo, Fortunato [13 ]
Bonato, Giulia [14 ]
Pellegrin, Serena [15 ]
Stanzial, Franco [16 ]
Posmyk, Renata [17 ]
Kaczorowska, Ewa [18 ]
Carecchio, Miryam [14 ]
Gos, Monika [19 ]
Rzonca-Niewczas, Sylwia [19 ]
Miano, Maria Giuseppina [4 ]
Murgia, Alessandra [1 ,2 ]
机构
[1] Univ Padua, Dept Womens & Childrens Hlth, Padua, Italy
[2] Pediat Res Inst, Citta Speranza, Padua, Italy
[3] Univ Padua, Dept Biomed Sci, Padua, Italy
[4] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, Naples, Italy
[5] St Georges Univ Hosp, Med Genet Unit, London, England
[6] Ist Sci Neurol Bologna, IRCCS, Bologna, Italy
[7] Fdn IRCCS CaGranda Osped Maggiore Policlin, Neurophysiopathol Unit, Milan, Italy
[8] Fdn IRCCS Ist Neurol Carlo Besta, Dept Pediat Neurosci, Milan, Italy
[9] Sapienza Univ Rome, Dept Human Neurosci, Unit Child Neurol & Psychiat, Rome, Italy
[10] Univ Campania Luigi Vanvitelli, Caserta, Italy
[11] Telethon Inst Genet & Med TIGEM, Pozzuoli, Italy
[12] ULSS 2 Treviso Hosp, Unit Med Genet, Treviso, Italy
[13] AORN San Pio, Med Genet Unit, Benevento, Italy
[14] Univ Padua, Dept Neurosci, Movement Disorders Unit, Padua, Italy
[15] Reg Hosp Bolzano, Dept Pediat, Child Neurol & Neurorehabil Unit, Bolzano, Italy
[16] Reg Hosp Bolzano, Dept Pediat, Genet Counseling Serv, Bolzano, Italy
[17] Med Univ Bialystok, Dept Clin Genet, Bialystok, Poland
[18] Med Univ Gdansk, Dept Biol & Med Genet, Gdansk, Poland
[19] Inst Mother & Child Hlth, Dept Med Genet, Dev Genet Lab, Warsaw, Poland
关键词
X-CHROMOSOME INACTIVATION; INTELLECTUAL DISABILITY; MUTATIONS; JARID1C; GENES; EXOME; IDENTIFICATION; FAMILY;
D O I
10.1038/s41431-022-01233-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.
引用
收藏
页码:202 / 215
页数:14
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