The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration

Table 2 Apparently homozygous variants in WES data of II:4 remaining after stringent filtering ( see Results )

Gene	Chr	Position (hg19)	Depth	Nucleotide alteration	Protein alteration	Sift	Polyphen	Condel	Mutation taster	Known Mendelian disease gene	Cosegreg. with disease	LOH region (Mb)
POMC	2	25384251	3	c. 503C > A	p. Ser168*	n.a.	n.a.	n.a.	delet	Early-onset obesity, adrenal insufficiency, red hair; ar	no	no
IMPG2	3	100995556	13	c. 535 T > G	p. Ser179Ala (intronic in most transcripts!)	tol	tol	tol	tol	Recessive retinitis, ar	n.d.	20
PHACTR1	6	12749777	4	delC	-	n.a.	n.a.	n.a.		no	n.d.	no
TAS2R38	7	141672688	34	c. 802C > T	p. Pro268Ser	tol	delet	delet	tol	no	n.d.	2.2
ERMP1	9	5832849	3	c. 179C > T	p. Ala60Val	tol	tol	tol	tol	no	n.d.	3
MRRF	9	125033286	112	c. 116A > G	p. His39Arg	tol	tol	tol	tol	no	n.d.	2.7
GLE1	9	131302562	18	c. 1211C > T	p. Ala404Val	tol	delet	delet	delet	Lethal arthrogryposis with anterior horn cell disease, ar	n.d.	3.7
HCFC2	12	104461873	60	c. 461A > T	p. Asn154Ile	delet	delet	delet	delet	no	n.d.	3.3
RBM19	12	114261045	18	c. 2867A > C	p. Gln956Pro	delet	tol	tol	tol	no	n.d.	3.6
SPTBN5	15	42174192	8	c. 2392_2393ins	p. Glu800Glyfs*41	n.a.	n.a.	n.a.	delet	no; LoF-tolerant gene!	no	no
DUS2L	16	68107968	14	c. 842C > G	p. Thr281Ser	tol	tol	tol	delet	no	n.d.	38
AP1G1	16	71784192	70	c. 1328A > T	p. Gln443Leu	tol	tol	tol	delet	no	n.d.	1.8
ZFHX3	16	72821594	76	c. 10804_10812del	p. Ala3602_Ala3604del	n.a.	n.a.	n.a.	tol	no	n.d.	8.6
*WWOX*	16	78142372	12	c. 160G > T	p. Arg54*	n.a.	n.a.	n.a.	delet	no	yes	54
ABCG1	21	43680243	3	c. 718G > A	p. Glu240Lys	tol	tol	tol	tol	no	n.d.	no

Variants in TAS2R38, GLE1, HCFC2, ZFHX3 and WWOX represented prime candidate variants because they localized within an LOH region and were predicted as pathogenic by most programs. Note that the POMC nonsense mutation was covered only 3 times, and Sanger sequencing revealed that it was in fact heterozygous which is compatible with POMC not localizing in an LOH region. The SPTBN5 frameshift mutation was found to be homozygous in II:4 and her healthy twin. SPTBN5 has been described as a non-essential gene that tolerates loss-of-function variants (LoF-tolerant) [15]. ar, autosomal recessive; n.a., not applicable: Assessment of deletions or insertions is out of scope for the methods of the prediction programs which require knowledge of the ancestral amino acids at that position (except Mutation Taster); delet, predicted as deleterious; tol, predicted as being tolerated; n.d., not defined: Segregation analysis was not carried out; LOH region: If a variant is embedded in a run of homozygous SNPs, indicating a loss of heterozygosity region, the extent of this region is given in Mb, megabases.

ISSN: 1750-1172