Application of whole‐exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability

Abstract

Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. © 2016 Wiley Periodicals, Inc.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

“…In general, a broad/bulbous nasal tip is present in the majority of patients (86%) together with ocular anomalies (such as hypertelorism, proptosis or deep set eyes and downslanting palpebral fissures [6,9,12]), mouth anomalies (down-turned corners of the mouth [9] or protruding tongue [6,7]) and ear anomalies (large, low set, rotated …), present in all five patients reported here. Joint hypermobility, a frequent finding in these five patients, has also been previously reported [9]. Other clinical findings previously reported are supernumerary nipple [6], cryptorchidism [6], and syndactyly [6].…”

“…Since 2015, around 80 cases of syndromic intellectual disability due to mutations at the KAT6A gene have been described in the literature, delineating a new syndrome with variable presentation ( Table 2 and Fig. 3) [4][5][6][7][8][9][10][11][12][13][14][15]. Here, we present 5 patients with de novo variants at KAT6A, four 'late truncating' and one missense variant, and we describe their clinical presentations, adding further clinical and molecular delineation to the KAT6A syndrome.…”

“…32; MIM # 616268). To date, a total of 79 patients have been reported [4][5][6][7][8][9][10][11][12][13][14][15]. All of them present with developmental delay (DD) or intellectual disability (ID) with speech delay.…”

How I manage children with neutropenia

“…There are also a number of syndromes involving the formation of lysosomal granules and vesicles within neutrophils and other leucocytes associated with milder forms of neutropenia (Dell'Angelica et al , ; Bellanné‐Chantelot et al , ; Gauthier‐Vasserot et al , ). Undoubtedly, new syndromes will be added to this list with increasing understanding of myeloid cells biology.…”

Severe congenital neutropenias

“…Whole exome sequencing would be a reasonable next step, if available, using global databases as control to identify common non-pathogenic variants; this approach can lead to the discovery of new causes for neutropenia. 106 It is usually best to review genetic findings in light of a registry and repository focused on the neutropenia-causing genes. In the European branch of the SCNIR, in 22 % (118/537) of the registered patients a genetic diagnosis could not be obtained.…”