Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

• Published in: American journal of medical genetics. Part A Vol. 185; no. 8; pp. 2345 - 2355
• Main Authors: Moirangthem, Amita, Mandal, Kausik, Saxena, Deepti, Srivastava, Priyanka, Gambhir, Poonam Singh, Agrawal, Neha, Shambhavi, Arya, Nampoothiri, Sheela, Phadke, Shubha R.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2021; Wiley Subscription Services, Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Alleles; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 3; Cytogenetics; developmental delay; DNA Copy Number Variations; Epigenetics; Etiology; exome sequencing; Facies; Female; Foxp1 protein; Gene regulation; Genetic Association Studies - methods; Genetic Heterogeneity; Genetic Predisposition to Disease; Genotype; Gigantism - diagnosis; Gigantism - genetics; Growth Charts; Humans; India; Infant; Intellectual disabilities; Intellectual Disability - diagnosis; Intellectual Disability - genetics; macrocephaly; Magnetic Resonance Imaging; Male; overgrowth; Phenotype; PTEN protein; Sequence Analysis, DNA; Sotos syndrome; Whole Exome Sequencing; India; developmental delay; exome sequencing; macrocephaly; Sotos syndrome; overgrowth
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.62241

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty‐one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K‐AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1‐related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first‐tier genomic test rather than CMA in OGID.