We describe two unrelated patients with severe microcephaly, ACC, and FBD-like cortical malformation, who have inherited deletions of 16p13.11 combined with truncating mutations in NDE1
. In all patients reported to date with the homozygous NDE1
phenotype, severe congenital microcephaly was present with profound intellectual disability and early onset seizures. In the first two reports, brain imaging showed severe microcephaly, extremely simplified gyral pattern, and ACC Alkuraya et al., 2011
; Bakircioglu et al., 2011
, as well as normal cortical ribbon thickness and small cerebellum. The malformation was designated microcephaly with lissencephaly or “microlissencephaly” Alkuraya et al., 2011
. On our review, the published images suggest a dysplastic cortex and proportionate cerebellum. We prefer to restrict use of the term “lissencephaly” to malformations in which the cerebral cortex is abnormally thick, so would describe the published images as showing microcephaly with a simplified gyral pattern and polymicrogyria-like cortical malformation. The third report shows the same severe microcephaly, growth deficiency, simplified gyral pattern and ACC, but also scalp rugae, a striking loss of brain tissue described as “microhydranencephaly” and a polymicrogyria-like cortical dysplasia Guven et al., 2012
Our two patients also had prominent loose scalp skin with scalp rugae. Brain MRI showed changes intermediate between the prior reports, including severe microcephaly, enlarged extra-axial fluid surrounding the brain that communicated with the lateral ventricles medially, severe simplified gyral pattern with obvious polymicrogyria-like cortical malformation, and ACC. The scalp rugae suggest late fetal loss of brain volume, and combined with the dramatic increased extra-axial space, resembles an FBD-like phenotype.
FBD refers to severe congenital microcephaly with a collapsed skull and prominent scalp rugae, increased extra-axial space, and cortical clefting. This combination of features has been previously regarded as occurring secondary to intrauterine brain disruption Russell et al., 1984
; Bönnemann and Meinecke, 1990
; Moore et al., 1990
; Alexander et al., 1995
; Schram et al., 2004
, and thus not genetic with a low recurrence risk. Our observations show that FBD can result from genetic causes with a high recurrence risk, although we still believe that some forms of FBD are indeed secondary to intrauterine brain disruption.
The malformations shown in the homozygous NDE1
reports most closely resemble the pattern associated with mutations of WDR62
Bilgüvar et al., 2010
; Yu et al., 2010
, while the associated growth deficiency resembles the pattern seen with severe microcephaly due to mutations of CENPJ
Al-Dosari et al., 2010
. Both WDR62
appear to be rare causes of severe congenital microcephaly reported in few pedigrees. Our data suggest that homozygous loss of NDE1
function may be a more common cause of autosomal recessive severe microcephaly, and may be present in outbred families. As the most common forms of severe congenital microcephaly are autosomal recessive, many clinicians do not order CMA to investigate them. We obtained an array in our proband because of the presence of ACC. We now prefer to order SNP microarrays in children with severe congenital microcephaly both to detect this microdeletion and to detect stretches of homozygosity that may represent loci harboring pathogenic mutations.
This is the second segmental duplication-mediated deletion associated with a recurrent autosomal recessive phenotype. The first is the bleeding disorder Bernard-Soulier syndrome, which is caused by homozygous or compound heterozygous mutations of the GP1BB
gene encoding the platelet glycoprotein GPIb/IX receptor. At least four patients have been reported in which the common 22q11.2 deletion served as one of the two mutations Budarf et al., 1995
; Ludlow et al., 1996
; Lascone et al., 2001
; Nakagawa et al., 2001
The inherited 16p13.11 deletions in our patients are additionally interesting because of the disparate phenotype reports associated with copy number variations at this locus. Many of the patients published have had relatively mild phenotypes such as ADHD, treatment-responsive epilepsies without cognitive impairment, mild microcephaly (OFC −3 SD), and isolated dysmorphologic findings such as cleft palate. It has been difficult to then reconcile the association of the same 16p13.11 deletion with the more severe neurodevelopmental findings of autism, intellectual disability, and schizophrenia. Our data suggest that these more severe phenotypes may be indicative of second genomic events—such as mutations of genes within the non-deleted 16p13.11 homolog.
Haploinsufficiency of NDE1
has been suggested as a possible cause for the developmental and neurologic phenotypes associated with 16p13.11 deletions de Kovel et al., 2010
; Heinzen et al., 2010
; Mefford et al., 2010
, although all parents carrying heterozygous mutations of the gene were reported to be normal Alkuraya et al., 2011
; Bakircioglu et al., 2011
; Guven et al., 2012
. Our informatics analysis of the gene content of the 16p13.11 region found evidence that several of the genes in the region, such as ABCC1
, and PDXDC1
have expression during brain development—as does NDE1
. These may be candidate genes for second-hit mutations in patients with deletions of 16p13.11 and more severe disorders of cortical connectivity such as autism, intellectual disability, and schizophrenia. Sequencing of these candidates in patients with severe neurodevelopmental phenotypes may yield more compelling explanations for these disorders.