Fetal phenotypes of Mendelian disorders: A descriptive study from India

Abstract

Objective: Exome sequencing (ES)-based diagnosis of Mendelian diseases in the fetus is limited by paucity of phenotypic information. This study reports the comprehensive phenotypes of some fetuses with Mendelian disorders. Methods: Next generation technology-based sequencing of all coding regions of the genome (Exome sequencing) or targeted gene sequencing using Sanger or next generation platforms was performed in a cohort of deeply phenotyped, cytogenetically normal fetuses with morphological defects. Prenatal ultrasonographic phenotypes and postmortem details including dysmorphology, histopathology, and radiography were ascertained. Novel candidate genes, novel/unusual findings, and unusual genotypes in cases with confirmed Mendelian disorders are described. Results: Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of aMendelian disorder with 50 pathogenic/likely pathogenic variants. The majority (87%) were autosomal recessive, 69% families were consanguineous, and 54% variants were novel. Dysmorphic syndromes, skeletal dysplasias, and metabolic disorders were the commonest disease categories, ciliopathies and dystroglycanopathies, commonest molecular categories. We describe the first fetal description of six monogenic diseases, and nine cases with novel histological findings. Nineteen cases had novel/unusual findings. Conclusion:This cohort demonstrates how deep fetal phenotypes of some Mendelian disorders can show novel/unusual findings, which have important implications for prenatal diagnosis of these conditions. Key pointsWhat's already known about this topic � Exome sequencing improves the genetic diagnostic yield in fetuses with abnormal perinatal phenotypes.� Knowledge of perinatal phenotypes of Mendelian disorders is limited and this compromises use of exome sequencing in prenatal period.� Dysmorphology plays an important role in recognition of Mendelian disorders.Neelam Saini and Vijaya Sree Venkatapuram have contributed equally

Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta‐analysis

“…The study selection process is demonstrated in the PRISMA flow diagram (Figure 1). Thirty studies fulfilled the eligibility criteria and were suitable for meta‐analysis (1583 cases) 4,7,9,10,22–47 . This included data from the NHS England prenatal exome sequencing pathway 39 .…”

“…For studies that met the inclusion criteria but provided inadequate phenotypic information, corresponding authors were contacted to request further data ( n = 57) of which 15 (26.3%) responded. Eleven studies provided extended data sets 4,9,10,27,29,37,40,43,46–48 . Supplementary Table highlights the characteristics of the included studies and Figure 2 shows the overall quality assessment.…”

“…Eleven studies provided extended data sets. 4,9,10,27,29,37,40,43,[46][47][48] Supplementary Table 1 highlights the characteristics of the included studies and Figure 2 shows the overall quality assessment.…”

Improving prenatal diagnosis through standards and aggregation

“…[7][8][9][10][11] Second, the spectrum of prenatal phenotypes, even of Mendelian disorders with well-described postnatal phenotypes, is not well described and can represent a phenotype expansion. [12][13][14][15] Emerging evidence, for example, suggests that SCN2A, an epilepsy gene, can present prenatally with central nervous system structural anomalies. [16][17][18] Third, prenatal phenotypes are largely limited to structural findings with no understanding of functional or cognitive differences.…”

Enhancement of phenotyping for fetal investigation using next‐generation sequencing

“…There is considerable interest in 'reverse phenotyping', whereby personalized diagnostic workflows permit the identification of previously unrecognized clinical signs of an unexpected underlying genetic diagnosis. Identification of an association of clinical postnatal structural and dysmorphological findings (by detailed clinical or postmortem examination), histology and additional radiological features (sometimes using postmortem magnetic resonance imaging (MRI)) with the prenatal ultrasound scan findings has been noted to improve the diagnosis of monogenic disorders [15][16][17] . This highlights the importance of a detailed and complete prenatal ultrasound examination performed in a tertiary center, with input from geneticists with expertise in prenatal management, to identify subtle fetal dysmorphology such as abnormalities of the fetal profile (e.g.…”