Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

被引：0

作者：

Kalm, Tassja ^{[1
]}

Schob, Claudia ^{[2
]}

Voeller, Hanna ^{[2
]}

Gardeitchik, Thatjana ^{[3
]}

Gilissen, Christian ^{[3
]}

Pfundt, Rolph ^{[3
]}

Kloeckner, Chiara ^{[4
]}

Platzer, Konrad ^{[4
]}

Klabunde-Cherwon, Annick ^{[5
]}

Ries, Markus ^{[5
]}

Syrbe, Steffen ^{[5
]}

Beccaria, Francesca ^{[6
]}

Madia, Francesca ^{[7
]}

Scala, Marcello ^{[7
,8
]}

Zara, Federico ^{[7
,8
]}

Hofstede, Floris ^{[9
]}

Simon, Marleen E. H. ^{[10
]}

van Jaarsveld, Richard H. ^{[10
]}

Oegema, Renske ^{[10
]}

van Gassen, Koen L. I. ^{[10
]}

Holwerda, Sjoerd J. B. ^{[10
]}

Barakat, Tahsin Stefan ^{[11
,12
,13
]}

Bouman, Arjan ^{[11
]}

Slegtenhorst, Marjon van ^{[11
]}

Alvarez, Sara ^{[14
]}

Fernandez-Jaen, Alberto ^{[15
]}

Porta, Javier ^{[16
]}

Accogli, Andrea ^{[17
,18
]}

Mancardi, Margherita Maria ^{[19
]}

Striano, Pasquale ^{[8
,20
]}

Iacomino, Michele ^{[7
]}

Chae, Jong-Hee ^{[21
,22
]}

Jang, SeSong ^{[21
]}

Kim, Soo Y. ^{[22
]}

Chitayat, David ^{[23
]}

Mercimek-Andrews, Saadet ^{[24
,25
]}

Depienne, Christel ^{[26
]}

Kampmeier, Antje ^{[26
]}

Kuechler, Alma ^{[26
]}

Surowy, Harald ^{[26
]}

Bertini, Enrico Silvio ^{[27
]}

Radio, Francesca Clementina ^{[28
]}

Mancini, Cecilia ^{[28
]}

Pizzi, Simone ^{[28
]}

Tartaglia, Marco ^{[28
]}

Gauthier, Lucas ^{[29
]}

Genevieve, David ^{[30
,31
]}

Tharreau, Mylene ^{[29
]}

Azoulay, Noy ^{[32
,33
]}

Zaks-Hoffer, Gal ^{[33
,34
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Ctr Expt Med, Inst Cellular & Integrat Physiol, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany

[3] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[4] Univ Leipzig, Med Ctr, Inst Human Genet, D-04103 Leipzig, Germany

[5] Univ Hosp Heidelberg, Div Pediat Epileptol, Ctr Paediat & Adolescent Med, D-69120 Heidelberg, Germany

[6] Terr Social Hlth Agcy, Dept Child Neuropsychiat, Epilepsy Ctr, I-46100 Mantua, Italy

[7] IRCCS Ist Giannina Gaslini, Med Genet Unit, I-16147 Genoa, Italy

[8] Univ Genoa, Dept Neurosci Rehabil Ophthalmol, Genet Maternal & Child Hlth, I-16145 Genoa, Italy

[9] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Gen Pediat, NL-3580 AB Utrecht, Netherlands

[10] Univ Med Ctr Utrecht, Dept Clin Genet, NL-3584 EA Utrecht, Netherlands

[11] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands

[12] Erasmus MC Univ Med Ctr, ENCORE Expertise Ctr Neurodev Disorders, NL-3000 CA Rotterdam, Netherlands

[13] Erasmus MC Univ Med Ctr, Dept Clin Genet, Discovery Unit, NL-3000 CA Rotterdam, Netherlands

[14] NIMGenetics, Genom & Med, Madrid 28108, Spain

[15] European Univ Madrid, Quironsalud Univ Hosp Madrid, Sch Med, Pediat Neurol Dept, Madrid 28224, Spain

[16] Genol Med, Genom, Malaga 29016, Spain

[17] McGill Univ, Montreal Childrens Hosp, Dept Specialized Med, Div Med Genet,Hlth Ctr, Montreal, PQ H4A 3J1, Canada

[18] McGill Univ, Dept Human Genet, Montreal, PQ H4A 3J1, Canada

[19] IRCCS Ist Giannina Gaslini, Child Neuropsychiat Unit, I-16147 Genoa, Italy

[20] IRCCS Ist Giannina Gaslini, Pediat Neurol & Neuromuscular Dis Unit, I-16147 Genoa, Italy

[21] Seoul Natl Univ, Coll Med, Dept Pediat, Seoul 110744, South Korea

[22] Seoul Natl Univ Hosp, Dept Genom Med, Rare Dis Ctr, Seoul 03080, South Korea

[23] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1E2, Canada

[24] Univ Toronto, Hosp Sick Kids, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[25] Univ Alberta, Fac Med & Dent, Dept Med Genet, Edmonton, AB T6G 2H7, Canada

[26] Univ Duisburg Essen, Univ Hosp Essen, Inst Human Genet, D-45122 Essen, Germany

[27] Bambino Gesu Pediat Hosp, Neuromuscular Disorders, IRCCS, I-00146 Rome, Italy

[28] Bambino Gesu Pediat Hosp, Mol Genet & Funct Genom, IRCCS, I-00146 Rome, Italy

[29] Univ Hosp Montpellier, Dept Mol Genet & Cytogen, Rare & Autoinflammatory Dis Unit, F-34295 Montpellier, France

[30] Montpellier Univ, Inserm U1183, Montpellier, France

[31] Univ Hosp Montpellier, Dept Clin Genet, F-34295 Montpellier, France

[32] Genet Inst Maccabi Hlth Serv, IL-7610000 Rehovot, Israel

[33] Beilinson Med Ctr, Raphael Recanati Genet Inst, Rabin Med Ctr, IL-49100 Petah Tiqwa, Israel

[34] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel

[35] Schneider Childrens Med Ctr Israel, Pediat Genet Unit, IL-4920235 Petah Tiqwa, Israel

[36] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[37] McGill Univ, Dept Pediat, Montreal, PQ, Canada

[38] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[39] McGill Univ, Hlth Ctr, Res Inst, Child Hlth & Human Dev Program, Montreal, PQ, Canada

[40] Childrens Mercy Kansas City, Genom Med Ctr, Dept Pediat, Kansas City, MO USA

[41] Univ Missouri Kansas City, UKMC Sch Med, Kansas City, MO USA

[42] Childrens Mercy Kansas City, Dept Pathol & Lab Med, Kansas City, MO USA

[43] Univ Med Ctr Hamburg Eppendorf, Dept Pediat, D-20246 Hamburg, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2024年 / 111卷 / 06期

关键词：

GLOBAL DEVELOPMENTAL DELAY; N-TERMINAL DOMAIN; A-TYPE CURRENTS; POTASSIUM CHANNELS; K+ CHANNELS; KV4.2; SUBUNITS; INACTIVATION; MODULATION; PHENOTYPE;

D O I：

10.1016/j.ajhg.2024.04.019

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1 , including two de novo missense variants, three maternally inherited protein -truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the a -subunit of Kv4.1 voltage -gated potassium channels. All variant -associated amino acid substitutions affect either the cytoplasmic N- or C -terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary b subunits. Variant -specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X -linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.

引用

页码：1206 / 1221

页数：17

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