Developmental delay referrals and the roles of Fragile X testing and molecular karyotyping: A New Zealand perspective

Abstract

Global developmental delay (GDD) affects ~1-3% of children, many of whom will also have intellectual disability (ID). Fragile X is the major genetic cause of GDD with mental retardation (MR) in males, accounting for ~20% of all X-linked MR. As Fragile X has serious genetic implications, the overwhelming majority of developmental delay (DD) cases referred to our laboratory are concerned with the exclusion of a diagnosis of Fragile X, along with simultaneous karyotype analysis to confirm chromosome aberrations. Critically, molecular laboratories have generally experienced a falling positive detection frequency of Fragile X. In this context, the recent implementation of array‑based techno-logy has significantly increased the likelihood of detecting chromosome aberrations that underpin DD. In the current study, we report a Fragile X mutation detection frequency for DD referrals that is comparable with the falling UK detection frequencies. In addition, we find that there is a 9‑fold greater likelihood of detecting clinically significant chromosomal aberrations than of detecting a full Fragile X mental retardation 1 (FMR1) gene CGG repeat expansion in cases referred on the basis of DD. We propose a more efficent sequential testing algorithm that involves an initial molecular karyotype, cascading to FMR1 gene analysis in the event of a negative result.

Elucidating the diagnostic odyssey of 22q11.2 deletion syndrome

“…However, nearly all individuals with an ID also have documented developmental delays [Doherty et al, 2013] and only a small proportion of the cohort had ID/DD but no major physical congenital anomalies. Also, we found that a diagnosis of ID/DD for any subgroup (pediatric to adult), did not shorten time to diagnosis.…”

Microduplication of 3p26.3 Implicated in Cognitive Development

“…The MRI scan of his brain was unremarkable and his creatinine kinase level was 35 U/L (normal age-specific range 30–150) [18]. Fragile X testing involved PCR amplification and then fluorescence-based capillary electrophoresis to determine the number of CGG repeats within the FMR-1 gene [19]. He was found to have a normal CGG repeat length of 30.…”

Η Γενετική Αρχιτεκτονική Των Εκ Γενετής Ανατομικών Και Νευρο-Αναπτυξιακών Διαταραχών

“…Με τη CMA μεθοδολογία, σε ασθενείς με νευροαναπτυξιακές ασθένειες, είναι δυνατό να εντοπιστούν διαγνωστικά ευρήματα σε ποσοστό 1520% 140; 142; 143 . Σε 19 μελέτες που αναφέρουν τη διαγνωστική ικανότητα του CMA και περιλαμβάνουν περισσότερα από 150 άτομα με νοητική και αναπτυξιακή καθυστέρηση, η διαγνωστική ικανότητα βρέθηκε να κυμαίνεται από 4.5-28% (κατά μέσο όρο 13.7%) [144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162] . Επίσης, σε 11 μελέτες που περιλαμβάνουν ασθενείς του αυτιστικού φάσματος (κάθε μελέτη περιλάμβανε τουλάχιστον 50 άτομα), η τεχνολογία CMA ανίχνευσε διαγνωστικά μοριακά ευρήματα σε 1.5 ως 20.5% (κατά μέσο όρο 8.1%) 149; 151; 152; 157; 162-168 .…”