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

Abstract

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.

Comprehensive Assessment of Fetal Bilateral Ventriculomegaly Based on Genetic Disorders, Cytomegalovirus Infection, Extra Prenatal Imaging and Pregnancy Outcomes in a Tertiary Referral Center

“…This microdeletion is related to Sotos syndrome, which may contribute to multisystem malformations, as well as growth and mental retardation. 32 , 33 The above noted pathogenic/likely pathogenic CNVs identified in the mild-to-moderate BVM cases of our study would have been misdiagnosed if karyotyping alone was performed. Therefore, CMA should be strongly recommended for prenatal diagnosis of fetal BVM, regardless of the degree of VM and the status of extra prenatal imaging.…”

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

“…Overgrowth is classically defined as occipitofrontal circumference (OFC) and height>97th centile or +2SD ( Moirangthem et al, 2021 ). Luscan-Lumish syndrome (also known as SETD2 -related neurological disorder) is mainly characterized by macrocephaly, tall stature and ID/DD, which is similar to a series of disorders with overgrowth and learning disability containing Sotos syndrome, Mylan syndrome, Weaver syndrome, Cohen-Gibson syndrome and so forth ( Pappas et al, 1993 ).…”

“…Luscan-Lumish syndrome (also known as SETD2 -related neurological disorder) is mainly characterized by macrocephaly, tall stature and ID/DD, which is similar to a series of disorders with overgrowth and learning disability containing Sotos syndrome, Mylan syndrome, Weaver syndrome, Cohen-Gibson syndrome and so forth ( Pappas et al, 1993 ). The molecular mechanisms of these disorders primarily involve in the epigenetic modulations (like STED2 , NSD1 , EZH2 ), transcription factors (like NFIA , NFIB , BRWD3 ) and PI3K-AKT signaling pathway (like PIK3CA , PTEN , MTOR ) ( Pappas et al, 1993 ; Moirangthem et al, 2021 ). It is noteworthy that some rare overgrowth syndromes remain molecularly uncharacterized.…”

An investigation of the etiology and follow‐up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant

“…Although the new OGID syndromes have been described in recent years, the molecular etiology is still unknown in approximately 50% (Tatton‐Brown et al, 2017). In a study with overgrowth syndrome, 42% were diagnosed with exome sequencing and CMA; Of these, 53% had mutations in genes involved in epigenetic regulation (Moirangthem et al, 2021). The diagnostic yield of WES, targeted gene sequencing and CMA in our OGID syndrome cohort was 88%; pathogenic variants in genes were associated with epigenetic regulation in 22/31 patients (70.9%), of which 81.8% were Sotos syndrome.…”