Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

Manickam, Kandamurugu; McClain, Monica R.; Demmer, Laurie A.; Biswas, Sawona; Kearney, Hutton M.; Malinowski, Jennifer; Massingham, Lauren J.; Miller, Danny E.; Yu, Timothy W.; Hisama, Fuki M.

doi:10.1038/s41436-021-01242-6

Cited by 277 publications

(247 citation statements)

References 92 publications

(98 reference statements)

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“…The literature indicates that high ID diagnostic yields are attained by applying the following sequential testing strategy using validated methods, after a detailed clinical evaluation: numeric and structural chromosomal abnormalities analysis, FXS testing, MECP2 (females) and PTEN genes investigation (in the presence of ASDs with macrocephaly) [ 183 ], CNVs screening by CMA [ 184 ] and exome sequencing [ 87 , 185 ]. As illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Intellectual disability genomics: current state, pitfalls and future challenges

et al. 2021

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Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery.

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Section: Discussionmentioning

confidence: 99%

Intellectual disability genomics: current state, pitfalls and future challenges

et al. 2021

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“…Establishing the diagnosis helped to provide closure for the family and informed recurrence risk for future pregnancies. In general, WES and WGS also provide important information regarding prognosis and surveillance measures and inform clinical management decisions (Meng et al, 2017;Clark et al, 2018;Manickam et al, 2021;NICUSeq study group et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies

et al. 2021

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Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C > T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.

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“…micropuce 1,11,14,15 , à un coût de plus en plus concurrentiel 2 . Les différentes catégories de phénotypes sont associées à des rendements diagnostiques différents 2,3,5 . Par exemple, le rendement peut être supérieur à 50 % chez les personnes qui présentent un handicap intellectuel de grave à profond, mais inférieur à 10 % dans la plupart des cohortes touchées par une seule anomalie congénitale majeure.…”

Section: Encadré 2 : Présentation Sommaire Du Counseling Génétiqueunclassified

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n a de plus en plus recours aux analyses génétiques de l'ADN constitutif des patients (de leur génome) dans la pratique médicale 1-3 . Séquencer le génome humain complet (environ 3,2 milliards de nucléotides) est désormais possible en quelques jours à quelques semaines, à un coût similaire à celui de certaines épreuves d'imagerie avancée ou d'une brève hospitalisation 3,4 . Le séquençage du génome est déjà intégré à des systèmes de soins de santé ailleurs dans le monde, particulièrement au Royaume-Uni 5 .

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