Whole-exome sequencing may help refine syndromic short stature diagnosis

medwireNews: Children who are born small for gestational age (SGA) and have syndromic short stature of unknown cause should be tested for genetic abnormalities using whole-exome sequencing (WES), researchers suggest.

While chromosomal microarray analysis for microscopic deletions or duplications, known as copy number variants, is the most common approach for identifying genetic markers in patients with short stature syndromes, the team hypothesised that WES may help identify an underlying cause after a negative genetic test of candidate genes (n=7) or a clinical diagnosis (n=37).

As reported in The Journal of Pediatrics, WES revealed that 34% of these patients had a known pathogenic or likely pathogenic variant form of one of 13 different genes previously associated with growth disturbance via an impact on cellular processes or DNA repair.

Two patients each carried a variant form of COL2A1 or SRCAP, while there were individual cases of mutations in AFF4, ACTG1ANKRD11BCL11BBRCA1CDKN1CGINS1INPP5KKIF11KMT2A and POC1A.

Alexander Augusto de Lima Jorge, from the University of Sao Paolo in Brazil, and co-investigators observe that the 34% rate is comparable with rates reported in previous research into children born SGA with syndromic short stature, whereas their own recent research gave a molecular genetic diagnosis rate of 15% for SGA children with isolated short stature.

This adds support for “higher rates of positive diagnosis among patients with intellectual disability, major malformation, facial dysmorphisms, skeletal dysplasia, familial cases and/or parental consanguinity”, they believe.

Using WES, the researchers were able to attribute short stature of prenatal onset to Floating-Harbor syndrome in two patients, while there were individual cases of Baraitser–Winter, KBG, Wiedemann–Steiner and SOFT syndrome, respectively.

One patient’s diagnosis was changed from Cornelia de Lange syndrome to CHOPS syndrome after identification of an AFF4 mutation, while a second patient with Silver-Russell syndrome had their diagnosis changed to IMAGE syndrome after WES detected a CDKN1C mutation.

In addition, one patient was diagnosed with Fanconi anaemia-like disease, one with spondyloeiphyseal dysplasia and another with Legg–Calve–Perthes disease, while a fourth patient was found to have muscular dystrophy with cataracts and intellectual disability. There were also individual cases of intellectual development disorder with T-cell abnormalities and other factors, and microcephaly.

“[W]e believe that with the popularization, price reduction, and an improvement at copy number variations analysis by WES, this will be the first line of investigation in syndromic cases of short stature without clinical recognition”, the researchers say.

They add: “Despite the need for more evidence of the cost effectiveness of WES, we believe that obtaining genetic results can save time by ending the diagnostic odyssey of a wide range of examinations and medical evaluations.

“Also, it can provide accurate information for genetic counseling and alter medical management.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

J Pediatr 2019; doi:10.1016/j.jpeds.2019.08.024
Martin Savage
Programme Director

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