The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD

Abstract

The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n = 83), and the other two comprising autism spectrum disorder (ASD) patients (total of n = 2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95%CI = 7.5-2147) but not for ASD (P = 0.4, OR = 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of patients with autistic features in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study.

Psychiatric phenotypes associated with hyperprolinemia: A systematic review

“…Like the previous group, mutations were present on both alleles, but were predicted to result in residual PRODH function (Bender et al, 2005;Guilmatre et al, 2010). Mutations included compound heterozygous missense mutations, hemizygous 350 kb PRODH deletions, or homozygous missense mutations in PRODH (Afenjar et al, 2007;Di Rosa et al, 2008;Di Rosa et al, 2014;Guilmatre et al, 2009;Guilmatre et al, 2010;Jacquet et al, 2002;Jacquet et al, 2005;Raux et al, 2007;Richard et al, 2016). Twenty-five of these 38 patients (287-1883 μmol/L) had a developmental phenotype such as developmental delay and/or intellectual disability (19 patients, Table 5).…”

“…Respectively: Case 2 and Case 3 correspond to Cases 003 and 001 in Raux et al (2007). Case 3 also corresponds to Case 001 in Richard et al (2016). Case 5 corresponds to the case in Humbertclaude et al Rosa et al (2008).…”

“…Six studies reported on eight children with hyperprolinemia (550-2,246 μmol/L), aged 4-14 years with PRODH mutations on both alleles, predicted to affect PRODH enzymatic function severely, with essentially undetectable PRODH activity in vitro (Afenjar et al, 2007;Bender et al, 2005;Guilmatre et al, 2010;Humbertclaude et al, 2001;Jacquet et al, 2002;Jacquet et al, 2003;Richard et al, 2016). Mutations included PRODH deletions, stop codons and a detrimental missense mutation (p.L441P).…”

“…Case 7 corresponds toJacquet et al (2003). Case 8 corresponds to Case 002 inRaux et al (2007), Patient 1 in DiRosa et al (2008), Patient 6 in DiRosa et al (2014), Patient Si30F5 inGuilmatre et al (2009), Patient Si30 inRichard et al (2016). e See also footnote 4, this…”

Comparação da heterogeneidade clínica entre portadores de desequilíbrios genômicos em 22q11.2 com base no motivo de encaminhamento para análise por microarray cromossômico

“…A HPI é uma condição recessiva, assim, a deleção do PRODH deve ser combinada com outro evento (geralmente mutação missense que reduz a atividade enzimática) no segundo alelo para causar um aumento no nível de prolina no plasma (Guilmatre et al, 2010), mas um estudo de caso e controle, comparando a frequência da deleção do PRODH (tanto em homozigose quanto em heterozigose), apontou que a deleção de pelo menos um alelo foi um forte fator de risco para HPI. Nesse estudo entretanto, associações com o TEA não foram validadas (Richard et al, 2016). O envolvimento da hiperprolinemia no determinismo do TEA é relacioanda ao fato de que a deficiência de PRODH em camundongos resulta em aumento da liberação de neurotransmissores em sinapses glutamatérgicas (Paterlini et al, 2005) e o do possível envolvimento do glutamato na patologia do TEA (Choudhury et al, 2012 (Rauch et al, 2005).…”