Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

Monies, Dorota; Abouelhoda, Mohamed; Assoum, Mirna; Moghrabi, Nabil; Rafiullah, Rafiullah; Almontashiri, Naif A M; Al‐Owain, Mohammed; Alzaidan, Hamad; Al-Sayed, Moeen; Subhani, Shazia; Cupler, Edward; Faden, Maha; Alhashem, Amal; Qari, Alya; Chedrawi, Aziza; Aldhalaan, Hisham; Kurdi, Wesam; Khan, Sameena; Rahbeeni, Zuhair; Alotaibi, Maha M.; Goljan, Ewa; Elbardisy, Hadeel; El‐Kalioby, Mohamed; Shah, Zeeshan Ali; Alruwaili, Hibah; Jaafar, Amal; Albar, Ranad; Akilan, Asma; Tayeb, Hamsa T.; Tahir, Asma; Fawzy, Mohamed; Nasr, Mohammed; Makki, Shaza; Abdullah, Aszrin; Akleh, Hanna; Yamani, Suad Al; Bubshait, Dalal; Mahnashi, Mohammed; Basha, Talal A.; Alsagheir, Afaf; Khaled, Musad Abu; Alsaleem, Khalid A.; Almugbel, Maisoon; Badawi, Manal; Bashiri, Fahad A.; Bohlega, Saeed; Sulaiman, Raashida; Tous, Ehab; Ahmed, S Faisal; Algoufi, Talal; Al‐Mousa, Hamoud; Alaki, Emadia; Alhumaidi, Susan; Alghamdi, Hadeel; Alghamdi, Malak; Sahly, Ahmed N.; Nahrir, Shapar; Al-Ahmari, Ali; Alkuraya, Hisham; Almehaidib, Ali; Abanemai, Mohammed; Alsohaibaini, Fahad; Al‐Saud, Bandar; Arnaout, Rand; Abdel-Salam, Ghada M H; Al-Dhekri, Hasan; AlKhater, Suzan; Alqadi, Khalid; Al‐Sabban, Essam; Alshareef, Turki; Awartani, Khalid; Banjar, Hanaa; Alsahan, Nada; Abosoudah, Ibraheem; Al-Ashwal, Abdullah A.; Aldekhail, Wajeeh; Al-Hajjar, Sami; Al‐Mayouf, Sulaiman M.; Alsemari, Abdulaziz; Alshuaibi, Walaa; Al-Tala, Saeed M.; Altalhi, Abdulhadi; Baz, Salah; Hamad, Muddathir H.; Abalkhail, Tariq; Alenazi, Badi; Alkaff, Alya; Almohareb, Fahad; Mutairi, Fuad Al; Alsaleh, Mona; Alsonbul, Abdullah; Alzelaye, Somaya; Bahzad, Shakir; Manee, Abdulaziz Bin; Jarrad, Ola; Meriki, Neama; Albeirouti, Bassem; Alqasmi, Amal; Balwi, Mohammed Al; Makhseed, Nawal; Hassan, Saeed‐Ul; Salih, Isam; Salih, Mustafa A.; Shaheen, Marwan; Sermin, Saadeh; Shahrukh, Shamsad; Hashmi, Shahrukh K.; Shawli, Ayman; Tajuddin, Ameen; Tamim, Abdullah; Alnahari, Ahmed; Ghemlas, Ibrahim; Hussein, Maged H.; Wali, Sami; Murad, Hatem; Meyer, Brian F.; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2019.09.019

Cited by 75 publications

(87 citation statements)

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“…This veri cation is crucial for the family counselling. Three familial cases were already reported in spite of a small number of total patients, which suggested parental mosaicism might be common in GNAO1 encephalopathy [2,4,6,17]. Therefore, testing for the mosaicism should be conducted if parents have plan to have another child.…”

Section: Discussionmentioning

confidence: 99%

Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

Kim

Shim

et al. 2020

Preprint

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Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations.Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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Section: Discussionmentioning

confidence: 99%

Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

Kim

Shim

et al. 2020

Preprint

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“…Perhaps unsurprisingly, the diagnostic yield of ES in consanguineous families is much higher than in outbred couples due to the overrepresentation of autosomal recessive conditions. While many large‐scale clinical studies quote an overall diagnostic yield of 22% to 30% with ES, subanalyses focused on consanguineous families have a higher diagnostic rate of up to 60% . This discrepancy reflects, in part, the higher likelihood that the cause of the disease in the patient is genetic in origin in the context of consanguinity.…”

Section: Introductionmentioning

confidence: 99%

When to think outside the autozygome: Best practices for exome sequencing in “consanguineous” families

et al. 2020

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Exome sequencing (ES) is an effective diagnostic tool with a high yield in consanguineous families. However, how diagnostic yield and mode of inheritance relate to family structure has not been well delineated. We reviewed ES results from families enrolled in the Care4Rare Canada research consortium with various degrees of consanguinity.We contrasted the diagnostic yield in families with parents who are second cousins or closer ("close" consanguinity) vs those more distantly related or from isolated populations ("presumed" consanguinity). We further stratified by number of affected individuals (multiple affected ["multiplex"] vs single affected [simplex]). The overall yield in 116 families was 45.7% (n = 53) with no significant difference between subgroups. Homozygous variants accounted for 100% and 75% of diagnoses in close and presumed consanguineous multiplex families, respectively. In simplex presumed consanguineous families, a striking 46.2% of diagnoses were due to de novo variants, vs only 11.8% in simplex closely consanguineous families (88.2% homozygous). Our data underscores the high yield of ES in consanguineous families and highlights that while a singleton approach may frequently be reasonable and a responsible use of resources, trio sequencing should be strongly considered in simplex families in the absence of confirmed consanguinity given the proportion of de novo variants. K E Y W O R D S

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“…We read with interest the study by Møller and colleagues 1. The isolation and relative homogeneity of the Saudi population enhance the potential to discover founder mutations, while its high rates of consanguinity enhances homozygosity even for typically dominant disease genes 2 3. We have previously explored the contribution of Lynch syndrome (LS) to colorectal cancer (CRC) based on ~800 Saudi patients 4.…”

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confidence: 99%

“…The PMS2 :c.1376C>G;p.S459X variant was the most commonly encountered LS variant (n=6), and we calculated its minor allele frequency at 0.0001. Importantly, we were able to identify a homozygous individual for PMS2 :c.1376C>G;p.S459X through a large scale whole-exome sequencing (WES) study 2. This individual presented at age 8 years with haematochezia and a typical picture of familial adenomatous polyposis (FAP) with thousands of polyps but negative adenomatous polyposis coli (APC ) testing for germline mutations and dMMR (figure 2).…”

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confidence: 99%

The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis

Siraj

Masoodi

et al. 2020

Gut

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Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

Cited by 75 publications

References 0 publications

Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

When to think outside the autozygome: Best practices for exome sequencing in “consanguineous” families

The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis

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