Validation of gene causality for neurological disorders

Bertoli-Avella, Aida M.; Al-Mulla, Fahd; Al-Twaijri, Waleed; Al-Thihli, Khalid; Al Shamsi, AM; Abdelrahman, H.A.; Al-Gazali, L; Shukla, Anju; Girisha, Katta; Garshasbi, Masoud; Housawi, Yousef; Al Mutairi, Fuad; Al-Sannaa, Nouriya; Alfadhel, Majid; Brandau, Oliver; Rolfs, Prof. Arndt; Elmonairy, A.A.; Marafi, Makia J.; Shawli, Aiman; Yüksel, Zafer; Yavuz, Halenur; Baldi, Caterina; Marais, Anett; Garcia-Aznar, Jose Maria; Grüning, Nana-Maria; Abbasi Moheb, L; Paknia, Omid; Kandaswamy, Krishna Kumar; Werber, Martin; Weiss, Maximilian E. R.; Oprea, Gabriela-Elena; Al Hakami, Fahad; Alshaikh, Nahla; Alameer, Seham; Bauer, Prof. Peter

Validation of gene causality for neurological disorders

Aida M. Bertoli-Avella, MD ¹ Zafer Yüksel, MD ¹ Halenur Yavuz ¹ Caterina Baldi, PhD ¹ Anett Marais ¹ Jose Maria Garcia-Aznar ¹ Nana-Maria Grüning ¹ L Abbasi Moheb ¹ Omid Paknia, PhD ¹ Krishna Kumar Kandaswamy, PhD ¹ Martin Werber ¹ Maximilian E. R. Weiss ¹ Gabriela-Elena Oprea, PhD ¹ Fahad Al Hakami ² Nahla Alshaikh ² Seham Alameer ² Aiman Shawli ² Makia J. Marafi ³ A.A. Elmonairy ³ Fahd Al-Mulla ⁴ Waleed Al-Twaijri ⁵ Khalid Al-Thihli ⁶ AM Al Shamsi ⁷ H.A. Abdelrahman ⁸ L Al-Gazali ⁸ Anju Shukla, MD ⁹ Katta Girisha, MD ⁹ Masoud Garshasbi ¹⁰ Yousef Housawi ¹¹ Fuad Al Mutairi ⁵ Nouriya Al-Sannaa ¹² Majid Alfadhel, MD ⁵ Oliver Brandau, MD ¹ Prof. Arndt Rolfs, MD ^{1, 13} Prof. Peter Bauer, MD ¹

¹ CENTOGENE AG ² Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia ³ Kuwait Medical Genetics Center ⁴ Genatak Center for Genomic Medicine, Kuwait City, Kuwait ⁵ King Abdullah International Medical Research Center (KAIMRC), Riyadh ⁶ Sultan Qaboos University Hospital, Muscat, Oman ⁷ Tawam Hospital Al Ain ⁸ United Arab Emirates University Al Ain ⁹ Manipal University ¹⁰ Tarbiat Modares University, DeNA Laboratory, Tehran, Iran ¹¹ King Fahad Specialist Hospital, Dammam, Saudi Arabia ¹² John Hopkins Aramco Health Care ¹³ University of Rostock

June 21, 2018

Validation of gene causality for neurological disorders by WES/WGS analyses in a diagnostic setting

Figure 1: Novel pedigrees as identified in our proprietary database CentoMD© for the indicated recessive disease genes

Figure 2: To-scale schemes of coding sequences (exon boundaries as stippled lines), critical protein domains, and pathogenic variants identified previously (black) and in CentoMD© (red)

Table 1: Origins of patients

Gene	Previously described patients	Patients from CentoMD© (bold=novel)
NUDT2	Saudi Arabia	Saudi Arabia
NKX6-2	India; Kenya/Tanzania; Morocco; Saudi Arabia	Kuwait; Oman; Saudi Arabia; United Arab Emirates
GTPBP2	Iran	Kuwait; Saudi Arabia
ACER3	Israel	India; Saudi Arabia

Table 2: Phenotypic features

Gene	Described previously	Novel in CentoMD©-listed patients
NUDT2	Intellectual disability	Low birth weight and height, muscular hypotonia, delayed motor and language development
NKX6-2	Hypomyelinating dystrophy, spastic ataxia	Mild dysmorphism, seizures, clinical regression
GTPBP2	Dystonia, ataxia, cognitive dysfunction; motor neuropathy, retinal abnormalities, sparse hair, brain iron accumulation	Skeletal anomalies, extra-neurological presentations, lack of clinical progression, no evidence for brain iron accumulation
ACER3	Progressive leukodystrophy (truncal hypotonia, appendicular spasticity, dystonia), short stature, late onset macrocephaly, facial dysmorphism	Underweight, lactic acidosis; delayed myelination; brain atrophy

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Validation of gene causality for neurological disorders

Validation of gene causality for neurological disorders by WES/WGS analyses in a diagnostic setting

Figure 1: Novel pedigrees as identified in our proprietary database CentoMD© for the indicated recessive disease genes

Figure 2: To-scale schemes of coding sequences (exon boundaries as stippled lines), critical protein domains, and pathogenic variants identified previously (black) and in CentoMD© (red)

Table 1: Origins of patients

Table 2: Phenotypic features

Table 3: Summary of novelties as extracted from CentoMD©